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Lung

The lungs are a pair of spongy, air-filled organs located in the thoracic cavity on either side of the heart, serving as the primary sites for gas exchange in the human respiratory system.^[1] They facilitate the intake of oxygen from inhaled air into the bloodstream and the expulsion of carbon dioxide from the blood into the exhaled air, primarily through microscopic air sacs called alveoli.^[2] Structurally, the right lung consists of three lobes (upper, middle, and lower) separated by oblique and horizontal fissures, while the left lung has two lobes (upper and lower) divided by an oblique fissure, allowing the left side to accommodate the heart.^[3] Each lung is enclosed by a double-layered pleura membrane—the visceral pleura covering the lung surface and the parietal pleura lining the thoracic wall—with a thin space between them filled with pleural fluid to minimize friction during breathing.^[1] The lungs receive deoxygenated blood via the pulmonary arteries from the right ventricle, which branches into capillaries surrounding the alveoli for oxygenation, and oxygenated blood returns to the left atrium through four pulmonary veins.^[3] Bronchial arteries provide oxygenated blood to the lung tissue itself, supporting its metabolic needs.^[3] Functionally, ventilation—the process of moving air into and out of the lungs—is driven by the diaphragm and intercostal muscles, creating negative pressure to draw air through the airways from the trachea to the bronchioles and ultimately to the approximately 480 million alveoli (range: 270–790 million).^[4] Gas exchange occurs across the thin alveolar walls, lined with type I pneumocytes for diffusion and type II pneumocytes that produce surfactant to prevent collapse, enabling efficient oxygen diffusion into capillaries and carbon dioxide removal.^[2] The lungs also play roles in regulating blood pH through gas exchange and can trap small emboli in the pulmonary circulation, though they are highly susceptible to environmental irritants and pathogens due to their large surface area of about 70 square meters.^[5]

Anatomy

Gross Anatomy

The lungs are paired, spongy organs occupying most of the thoracic cavity, positioned on either side of the mediastinum and protected by the rib cage. Each lung has a broad base that conforms to the convex dome of the diaphragm and an apex that extends superiorly above the first rib into the root of the neck. The right lung is larger, shorter, and broader than the left, reflecting the asymmetric positions of underlying organs such as the liver and heart. The costal surface of each lung contacts the ribs, the diaphragmatic surface rests on the diaphragm, and the mediastinal surface faces the midline structures.^[3] Each lung is invested by two pleural layers: the visceral pleura, which closely adheres to the lung surface and extends into the fissures, and the parietal pleura, which lines the thoracic wall, superior surface of the diaphragm, and mediastinum. The narrow pleural cavity between these layers contains a thin film of serous fluid that minimizes friction during respiratory movements and helps maintain lung apposition to the chest wall. The root of the lung, comprising the main bronchus, pulmonary vessels, and nerves, attaches at the hilum—a wedge-shaped depression on the mediastinal surface—securing the lungs to the mediastinum anterior to the vertebral bodies of T5 to T7.^[3] The right lung consists of three distinct lobes—the upper, middle, and lower—separated by an oblique fissure and a horizontal fissure. The oblique fissure begins at the hilum and courses posteriorly and inferiorly to the diaphragm, dividing the lower lobe from the upper and middle lobes, while the horizontal fissure arises anteriorly from the oblique fissure and extends horizontally to the chest wall, separating the upper lobe from the middle lobe. In comparison, the left lung has two lobes—the upper and lower—divided solely by an oblique fissure that mirrors the position of the right lung's oblique fissure. The left upper lobe features a prominent cardiac notch, a concave indentation along its inferior anterior margin that accommodates the cardiac apex, and includes the lingular segment as a medial extension analogous to the right middle lobe.^[3] Bronchopulmonary segments represent the functional gross structural units of the lungs, each forming a discrete, pyramidal portion of lung parenchyma supplied by a tertiary (segmental) bronchus entering at the segment's apex. The right lung contains 10 such segments: three in the upper lobe (apical, posterior, anterior), two in the middle lobe (lateral, medial), and five in the lower lobe (superior, medial basal, anterior basal, lateral basal, posterior basal). The left lung has 8 to 10 segments: typically four in the upper lobe (apicoposterior, anterior, superior lingular, inferior lingular) and four to five in the lower lobe (superior, anteromedial basal, lateral basal, posterior basal), with variability arising from fusion of the superior and medial basal segments. These segments enable precise localization of pathology and surgical resection while preserving adjacent lung tissue.^[3]

Microscopic Anatomy

The microscopic anatomy of the lung encompasses the cellular and tissue-level organization that facilitates its respiratory functions. The respiratory epithelium varies along the airway tree to support conduction and eventual gas exchange. In the bronchi, the epithelium is primarily ciliated pseudostratified columnar, featuring goblet cells that secrete mucus to trap particulates and cilia that propel them upward.^[6] As airways narrow into bronchioles, the epithelium transitions to simple cuboidal or columnar cells, retaining cilia in larger bronchioles but losing them in terminal bronchioles, which lack cartilage and glands.^[7] In alveoli, the epithelium consists of thin simple squamous cells optimized for diffusion.^[6] The bronchial airways progress hierarchically from larger, cartilage-supported bronchi to smaller, non-cartilaginous structures. Bronchi contain incomplete rings or plates of hyaline cartilage embedded in a fibrous connective tissue matrix, maintaining airway patency, while smooth muscle layers allow dynamic constriction.^[5] These give way to bronchioles, which rely on elastic recoil and smooth muscle for support, culminating in terminal bronchioles as the end of the purely conductive zone.^[7] Respiratory bronchioles mark the transition to gas exchange, featuring scattered alveolar outpouchings within their walls and a mix of cuboidal epithelial cells.^[5] Alveoli form the functional units of gas exchange, characterized by polyhedral airspaces lined by specialized pneumocytes and supported by a minimal interstitium. Type I pneumocytes, flat squamous cells covering approximately 95% of the alveolar surface (though comprising only 40% of the cell population), form a thin barrier for oxygen and carbon dioxide diffusion.^[8] Type II pneumocytes, cuboidal cells occupying the remaining surface, produce and secrete pulmonary surfactant—a phospholipid-protein complex stored in lamellar bodies—that reduces surface tension to prevent alveolar collapse during exhalation.^[8] Alveolar macrophages, mobile phagocytic cells within the alveolar lumen, engulf debris, pathogens, and surfactant remnants to maintain sterility and clear airspace.^[9] The lung's connective tissue framework provides structural integrity and elasticity throughout its parenchyma. Composed mainly of collagen and elastic fibers interwoven in the interstitium—a delicate network between alveoli, vessels, and airways—this matrix supports expansion during inhalation and recoil during exhalation.^[10] Elastic fibers, abundant in the alveolar septa and visceral pleura, enable the lung's compliance, while collagen imparts tensile strength to withstand mechanical stresses.^[11] The healthy lung harbors a low-biomass microbiota, distinct from the upper respiratory tract, with bacterial diversity dominated by phyla such as Bacteroidetes, Firmicutes, and Proteobacteria at densities of 10³ to 10⁵ microbes per gram of tissue.^[12] This resident community contributes to homeostasis by modulating innate and adaptive immunity, promoting immune tolerance to prevent excessive inflammation, and competing with pathogens to maintain a balanced pulmonary environment.^[13]

Blood and Nerve Supply

The pulmonary arteries originate from the main pulmonary trunk, which arises from the right ventricle of the heart, and carry deoxygenated blood to the lungs for oxygenation.^[14] These arteries branch into lobar and segmental arteries that follow the bronchial tree, further dividing into pulmonary arterioles and an extensive capillary network surrounding the alveoli to facilitate gas exchange.^[3] The pulmonary veins collect oxygenated blood from the alveolar capillaries and return it to the left atrium of the heart.^[15] Typically, there are four pulmonary veins that drain into the left atrium, two from each lung—a superior vein draining the upper lobe (and middle lobe on the right) and an inferior vein draining the lower lobe—though variations such as a separate middle vein on the right can result in five veins.^[16]^[17] The bronchial arteries provide oxygenated systemic blood to nourish the lung tissue, including the bronchi, connective tissue, and visceral pleura, distinct from the pulmonary circulation's role in gas exchange.^[18] These arteries typically arise from the descending thoracic aorta (one to two on the right, often from the first right posterior intercostal artery or directly from the aorta, and one to two on the left directly from the aorta), while the bronchial veins drain deoxygenated blood primarily into the azygos vein on the right and the hemiazygos or accessory hemiazygos veins on the left, with some drainage into pulmonary veins.^[19] The lungs receive autonomic innervation primarily through the pulmonary plexus, which integrates sympathetic and parasympathetic fibers to regulate airway tone and vascular resistance.^[3] Sympathetic nerves, derived from the upper thoracic sympathetic chain and traveling via the pulmonary plexus, promote bronchodilation and vasoconstriction in pulmonary vessels by releasing norepinephrine, which acts on beta-2 adrenergic receptors in airways and alpha-1 receptors in vessels.^[3] Parasympathetic innervation occurs via the vagus nerve (cranial nerve X), forming the anterior and posterior pulmonary plexuses, and induces bronchoconstriction through acetylcholine release on muscarinic receptors, along with increased glandular secretion and vasodilation in bronchial vessels.^[3] Lymphatic drainage from the lungs begins in superficial and deep plexuses within the visceral pleura and lung parenchyma, converging toward the hilum.^[19] Superficial lymphatics drain the pleural surfaces, while deep lymphatics follow the bronchi and pulmonary vessels; both systems empty into bronchopulmonary (hilar) lymph nodes located at the lung hilum, which then drain into superior and inferior tracheobronchial nodes and subsequently to mediastinal nodes (including paratracheal and subcarinal), ultimately reaching the thoracic duct or right lymphatic duct.^[19]

Variations

Anatomical variations in lung structure occur across individuals and populations, primarily affecting fissures, lobes, and bronchopulmonary segments, which can influence imaging interpretation and surgical planning. These variations arise from differences in the development of pleural invaginations and vascular positioning, leading to deviations from the typical three-lobed right lung and two-lobed left lung configuration. While the standard lung anatomy features complete oblique and horizontal fissures on the right and an oblique fissure on the left, incomplete or absent fissures are common, with the horizontal fissure on the right being absent in approximately 10-20% of cases based on cadaveric and CT studies.^[20]^[21] One notable variation is the azygos lobe, a rare accessory lobe in the right upper lung formed when the azygos vein fails to migrate medially during development, creating a mesoazygos fold that separates a portion of the apical segment. This occurs in about 0.4-1.2% of individuals, more frequently detected on high-resolution CT scans than on plain radiographs, and is typically asymptomatic but can mimic mediastinal masses on imaging.^[22]^[23] Fissure completeness varies widely, with incomplete horizontal fissures reported in up to 34% of right lungs in some cadaveric series, often resulting in partial fusion of the upper and middle lobes. Accessory fissures, such as the inferior accessory fissure separating the medial basal segment of the lower lobe, occur in 3-7% of lungs and are more common on the right side. These accessory structures enhance lobar independence but may complicate procedures like lung volume reduction surgery.^[24]^[25] Segmental variations include the absence of certain bronchopulmonary segments, such as the middle lobe segment on the right, which can result from incomplete fissuring and lead to a bilobed appearance, observed in isolated case reports and small series. Supernumerary segments, where additional subsegments arise due to extra bronchial branching, are less common and contribute to the variability in left lung segment count (typically 8-10), potentially affecting ventilation patterns.^[26]^[20] Population differences influence the incidence of these variations; for instance, African American individuals exhibit higher fissure completeness across all major fissures compared to non-Hispanic White individuals, with median integrity scores differing significantly in large cohort studies. Such ethnic disparities may stem from genetic factors affecting pleural development, though further research is needed to elucidate underlying mechanisms. Studies in South Asian and African populations report higher rates of accessory fissures, up to 18% in some samples.^[27]^[28]

Development

Embryonic Development

The development of the lungs begins during the embryonic stage of human gestation, around week 4, when the respiratory diverticulum, or lung bud, emerges as an outpouching from the ventral wall of the foregut endoderm.^[29] This bud rapidly bifurcates into the left and right primary bronchial buds, which separate from the esophagus to form the trachea, marking the initial separation of the respiratory and digestive tracts.^[30] By week 5, secondary bronchi develop, followed by tertiary buds by week 6, establishing the foundational bronchopulmonary segments and initiating branching morphogenesis that will shape the conducting airways.^[29] This branching continues extensively during the pseudoglandular stage, from weeks 5 to 17, where the lung buds generate up to 20 generations of bronchi and bronchioles, forming the bronchial tree while the epithelium differentiates into ciliated, goblet, and basal cells.^[30] Cartilage, smooth muscle, and intrapulmonary arteries also begin to form around the developing airways, creating a glandular-like appearance, though no gas exchange is possible at this stage due to the absence of alveoli.^[29] Transitioning into the canalicular stage (weeks 16 to 25), terminal bronchioles elongate into primitive acini, with respiratory bronchioles and alveolar ducts emerging alongside extensive vascularization from the pulmonary arteries, which invade the mesenchyme to form a capillary network essential for future oxygenation.^[30] Type II pneumocytes appear around week 20, developing lamellar bodies that initiate limited surfactant synthesis, while primitive alveoli start to form, enabling rudimentary gas exchange if premature birth occurs.^[29] The saccular stage, spanning weeks 24 to 38 (or birth), involves further expansion of the airspaces into terminal sacs or saccules, with thinning of the interstitium and differentiation of type II cells into flattened type I pneumocytes to establish the blood-air barrier.^[30] Surfactant production ramps up significantly from week 24 onward, reaching adequacy by week 32, which is crucial for reducing surface tension in the alveoli and facilitating the first breaths after birth.^[29] Throughout these prenatal stages, the fetus relies entirely on placental gas exchange for oxygenation and carbon dioxide removal, as the pulmonary circulation remains underdeveloped and fluid-filled until birth.^[29] Maternal vitamin A deficiency during early gestation disrupts retinoic acid signaling, a key regulator of foregut patterning, leading to abnormalities such as tracheoesophageal fistula or lung hypoplasia due to impaired lung bud formation and branching.^[31]

Postnatal Development

Postnatal lung development primarily involves the alveolarization phase, which begins at birth and continues until approximately age 8 years. At birth, the human lung contains an estimated 20 to 50 million alveoli, representing only a fraction of the adult complement. During this period, the number of alveoli increases dramatically through septation of the saccular walls, reaching about 300 million by age 8, thereby expanding the gas exchange surface area to support growing metabolic demands.^[32]^[33] This process occurs in waves, with rapid formation in the first few years followed by slower maturation, ensuring the lung architecture accommodates the child's expanding body size. Lung volume expands proportionally to overall body growth from infancy through adolescence, driven by increases in thoracic cavity dimensions and parenchymal tissue. This growth trajectory results in lung function peaking in early adulthood, around 20 to 25 years of age, when maximal vital capacity and diffusing capacity are achieved.^[34]^[35] Beyond this peak, subtle structural changes begin, including a gradual loss of elastic recoil in the lung parenchyma starting after age 30, which contributes to reduced compliance and efficiency in gas exchange.^[36] Aging further impacts lung structure, with alveolar surface area declining by approximately 4% per decade after age 30 due to airspace enlargement and mild emphysematous changes in otherwise healthy individuals. This reduction, from about 75 m² in young adulthood to around 60 m² by age 70, diminishes overall respiratory reserve without significant alveolar wall destruction.^[37] These changes are accompanied by stiffening of the chest wall and weakening of respiratory muscles, leading to a progressive decline in forced vital capacity of roughly 20-30 mL per year after the peak.^[38] Environmental factors, such as exposure to air pollution, can impair postnatal lung growth by disrupting alveolar septation and reducing lung function trajectories. For instance, chronic exposure to particulate matter and traffic-related pollutants from childhood through adolescence has been linked to deficits in forced expiratory volume, equivalent to months or years of normal growth loss.^[39]^[40] The lungs also demonstrate plasticity in response to extreme environments postnatally. In individuals ascending to high altitudes, adaptive responses include increased ventilation and enhanced pulmonary diffusion capacity, with children raised at altitude developing larger lung volumes and thoracic dimensions compared to sea-level peers.^[41] Similarly, repeated breath-hold diving induces physiological adaptations such as expanded lung capacity and improved oxygen conservation, though these are modulated by training and individual variability rather than permanent structural remodeling.^[42]

Physiology

Gas Exchange

Gas exchange in the lungs occurs primarily through the diffusion of oxygen (O₂) and carbon dioxide (CO₂) across the thin alveolar-capillary membrane, enabling the uptake of O₂ from inspired air into the bloodstream and the elimination of CO₂ produced by tissue metabolism.^[43] This process is highly efficient due to the vast surface area of the alveoli, approximately 70 square meters in adults, and the minimal thickness of the diffusion barrier, about 0.3 micrometers.^[44] The alveoli, as the functional units of gas exchange, consist of a single layer of epithelial cells surrounded by endothelial cells of pulmonary capillaries, facilitating rapid equilibration of gases between alveolar air and blood.^[43] The rate of gas diffusion across the alveolar-capillary membrane is governed by Fick's law of diffusion, which states that the volume of gas transferred (V) is proportional to the surface area available for diffusion (A), the diffusion coefficient of the gas (D), and the partial pressure difference across the membrane (P₁ - P₂), while being inversely proportional to the membrane thickness (T).^[44] Mathematically, this is expressed as:

V = \frac{A}{T} \cdot D \cdot (P_1 - P_2)

For O₂ and CO₂, D is higher for CO₂ due to its greater solubility in water, allowing CO₂ to diffuse about 20 times faster than O₂ despite a smaller partial pressure gradient.^[45] At sea level, the partial pressure of O₂ in the alveoli (PAO₂) is approximately 100 mmHg, while the partial pressure of CO₂ (PACO₂) is about 40 mmHg, creating favorable gradients for O₂ entry into deoxygenated venous blood (PvO₂ ≈ 40 mmHg, PvCO₂ ≈ 45 mmHg) and CO₂ exit.^[46] Optimal gas exchange requires effective matching of ventilation (airflow to alveoli) and perfusion (blood flow through pulmonary capillaries), quantified by the ventilation-perfusion ratio (V/Q).^[47] In a healthy lung at rest, total alveolar ventilation is about 4 L/min and pulmonary blood flow is 5 L/min, yielding an overall V/Q ratio of approximately 0.8, which balances the higher capacity for CO₂ elimination with O₂ uptake needs.^[48] This ratio varies regionally due to gravity, with higher V/Q in apical zones and lower in basal zones, but physiological mechanisms like hypoxic vasoconstriction help minimize mismatches to maintain efficient gas transfer.^[49] Once in the blood, O₂ binds to hemoglobin in red blood cells, with each molecule carrying up to four O₂ molecules, achieving near-full saturation (about 97-98%) in arterial blood due to the high PAO₂.^[43] The Bohr effect enhances CO₂ unloading in tissues and O₂ loading in the lungs by modulating hemoglobin's oxygen affinity: in the pulmonary capillaries, the lower PCO₂ and higher pH shift the oxygen-hemoglobin dissociation curve leftward, promoting O₂ binding, while the reverse occurs in systemic tissues.^[50] This allosteric regulation, first described by Christian Bohr in 1904, increases the efficiency of respiratory gas transport under physiological conditions.^[51] Pulmonary surfactant, a phospholipid-protein complex secreted by type II alveolar cells, plays a critical role in gas exchange by reducing surface tension at the air-liquid interface within alveoli, preventing collapse (atelectasis) during expiration.^[52] Without surfactant, surface tension forces would cause smaller alveoli to empty into larger ones per Laplace's law (P = 2T/r, where P is pressure, T is tension, and r is radius), leading to uneven ventilation and impaired diffusion; surfactant lowers T disproportionately in smaller alveoli, stabilizing them and maintaining a uniform V/Q distribution.^[53] This reduction in surface tension can decrease it by up to 15-fold, ensuring stable alveolar patency essential for continuous gas exchange.^[54]

Protective Functions

The lungs employ multiple innate defense mechanisms to protect against inhaled pathogens, particulates, and environmental irritants, maintaining airway patency and preventing infection. These include physical barriers, cellular effectors, and biochemical modulators that collectively trap, neutralize, and expel harmful agents before they can establish infection or cause damage.^[55] Mucociliary clearance serves as the primary physical barrier in the conducting airways, where ciliated epithelial cells and mucus work in concert to trap and remove inhaled particles. Mucus, a viscoelastic gel composed primarily of water (97%) with mucins such as MUC5AC and MUC5B, forms a protective layer approximately 2-5 µm thick in the trachea, secreted by goblet cells and submucosal glands. This layer captures microbes, dust, and allergens upon inhalation. Coordinated beating of cilia—hair-like structures 6.5-7 µm long with a 9+2 microtubule axoneme powered by dynein arms and ATP—at frequencies of 10-20 Hz propels the mucus layer cephalad in metachronal waves, forming the mucociliary escalator that transports trapped debris toward the pharynx at rates of about 5.5 mm/min for swallowing or expectoration. This process efficiently clears over 90% of inhaled particles under normal conditions, as detailed in foundational studies on airway epithelial function.^[55]^[56]^[57] Alveolar macrophages, resident sentinel cells in the distal lung, provide crucial phagocytic defense in the gas-exchange regions. These mononuclear phagocytes, comprising up to 15% of cells in the alveolar space, engulf and degrade microbes, apoptotic cells, particulate matter, and excess surfactant through pattern recognition receptors such as toll-like and scavenger receptors, utilizing pseudopods and lysosomal enzymes for intracellular killing. In response to pathogens, they produce pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 to recruit neutrophils and amplify adaptive immunity, while also secreting anti-inflammatory mediators like IL-10 and TGF-β to resolve responses and prevent excessive tissue damage. This dual role maintains pulmonary homeostasis and limits inflammation, as evidenced by their high phagocytic efficiency against bacteria like Pseudomonas aeruginosa.^[9]^[58]^[59] Mechanical reflexes such as coughing and sneezing augment clearance by generating forceful expiratory flows to dislodge irritants from the airways. The cough reflex, triggered by rapidly adapting receptors (RARs) and C-fibers in the trachea, carina, and intrapulmonary airways sensing mechanical or chemical stimuli, involves vagal afferents signaling to the medullary cough center, followed by efferent activation of expiratory muscles to produce airflow velocities up to 100 km/h (28 m/s), effectively expelling mucus and particulates.^[60] Similarly, the sneeze reflex, initiated by trigeminal nerve stimulation of nasal mucosa receptors in response to irritants like allergens or pathogens, engages brainstem circuits including the sneeze-evoking zone to generate nasal airflow exceeding 100 km/h, propelling droplets and debris outward to protect the lower airways. These reflexes are essential for preventing aspiration and pathogen entry, with cough serving as the dominant watchdog of lung health.^[61]^[62] Biochemical defenses in airway secretions further enhance protection through immunoglobulin A (IgA) and surfactant proteins. Secretory IgA (sIgA), the predominant immunoglobulin in mucosal secretions, is produced by local plasma cells and transported via the polymeric Ig receptor to the airway lumen, where it agglutinates pathogens and neutralizes viruses such as influenza by blocking epithelial adherence and facilitating immune exclusion. Surfactant proteins SP-A and SP-D, collectin family members secreted by alveolar type II cells, bind microbial carbohydrates via C-type lectin domains to promote opsonization; SP-A enhances phagocytosis of bacteria like Haemophilus influenzae and viruses including respiratory syncytial virus by alveolar macrophages, while SP-D aggregates pathogens and boosts uptake of Pseudomonas aeruginosa, modulating inflammation without complement involvement. These components collectively inhibit microbial invasion and support mucociliary transport.^[63]^[64]^[65] Airway surface liquid (ASL) pH regulation provides an additional antimicrobial barrier by creating an inhospitable environment for bacterial growth. Normally maintained at approximately 7.2 through CFTR-mediated bicarbonate (HCO₃⁻) secretion by airway epithelia, ASL pH inhibits pathogens like Staphylococcus aureus by enhancing the activity of antimicrobial peptides such as β-defensin-3 and LL-37, which show reduced efficacy below pH 6.8. Acidification impairs bacterial killing, as demonstrated in models where lowering pH halves clearance rates, underscoring pH's role in innate defense.^[66]^[67]

Other Physiological Roles

The lungs play a crucial role in the renin-angiotensin system through the expression of angiotensin-converting enzyme (ACE) on the surface of pulmonary endothelial cells, where it catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor that helps regulate systemic blood pressure.^[68] This enzymatic activity is particularly prominent in the pulmonary capillaries, which receive the entire cardiac output, ensuring efficient production of angiotensin II for circulation-wide effects on vascular tone and fluid balance.^[69] Disruption of this process, as seen with ACE inhibitors, underscores the lung's contribution to cardiovascular homeostasis beyond respiration.^[70] Lung tissue also serves as a site for the synthesis of bioactive lipid mediators, including prostaglandins and leukotrienes, derived from arachidonic acid metabolism via cyclooxygenase and lipoxygenase pathways. Alveolar type II cells and other resident cells in the lung parenchyma produce these eicosanoids, which modulate local inflammation, vascular permeability, and bronchomotor tone.^[71] For instance, prostaglandin E2 exerts bronchodilatory and anti-inflammatory effects, while leukotrienes like LTC4 promote vasoconstriction and mucus secretion, highlighting the lungs' involvement in fine-tuning pulmonary responses to stimuli.^[72] The pulmonary capillaries function as a mechanical filter, trapping small blood clots (thrombi) and gas bubbles that enter the venous circulation, preventing their passage to the systemic arterial system. This filtration capacity relies on the extensive capillary network and endothelial interactions that promote clot lysis or bubble dissolution, with larger emboli potentially overwhelming this barrier and causing hemodynamic compromise.^[73] In cases of venous gas embolism, the lungs absorb or trap microbubbles, mitigating risks like paradoxical embolism.^[74] During expiration, the lungs provide the subglottic airflow necessary for vocalization, as controlled exhalation drives air across the vocal cords, causing their vibration to produce sound. This process coordinates respiratory mechanics with laryngeal adduction, enabling phonation primarily on the expiratory phase to sustain voice output.^[75] Additionally, the lungs contribute to blood pH buffering by excreting carbon dioxide (CO2), the primary volatile acid, through ventilation, which shifts the bicarbonate buffer equilibrium to maintain acid-base homeostasis. Hyperventilation rapidly lowers blood PCO2 to raise pH in alkalotic states, while hypoventilation retains CO2 to acidify blood, demonstrating the pulmonary system's key role in respiratory compensation for pH disturbances.^[76]

Genetics

Gene Expression

Gene expression in the lung is tightly regulated to support its diverse cellular functions, with key transcription factors acting as master regulators during development and maintenance. FOXF1, a forkhead box transcription factor, plays a critical role in promoting lung morphogenesis by regulating mesenchymal-epithelial signaling and stimulating cellular proliferation in fetal lung mesenchyme.^[77] Similarly, NKX2.1 (also known as TTF-1), a homeobox transcription factor, serves as a master regulator of lung epithelial differentiation, marking the initial lung buds and controlling the specification of respiratory endoderm from early embryonic stages.^[78] These factors orchestrate the expression of downstream genes essential for lung bud formation and branching morphogenesis.^[79] In alveolar type II (AT2) cells, which are responsible for surfactant production, the genes encoding pulmonary surfactant proteins are prominently expressed. The SFTPA, SFTPB, SFTPC, and SFTPD genes produce apolipoproteins that constitute a significant portion of surfactant, aiding in reducing surface tension and innate immune defense within the alveoli.^[80] These genes are selectively transcribed in AT2 cells, with SFTPA1 and SFTPA2 encoding collectin proteins involved in pathogen recognition, while SFTPB and SFTPC contribute to lipid organization for efficient gas exchange.^[81] Expression levels of these genes are highest in the distal lung regions, reflecting their role in alveolar stability.^[82] Spatial patterns of gene expression in the lung align with functional zonation, with higher expression of gas exchange-related genes in the alveoli compared to the airways. In alveolar regions, genes such as AGER (encoding advanced glycation endproduct-specific receptor) are highly enriched in alveolar type I (AT1) cells, facilitating thin barrier formation for optimal gas diffusion.^[83] AQP5 (aquaporin 5) is highly enriched in AT1 cells, facilitating water transport for optimal gas diffusion.^[84] Surfactant genes like SFTPB further predominate in alveoli to support surface tension reduction.^[85] In contrast, mucin genes such as MUC5AC are predominantly expressed in the surface epithelium of central conducting airways, where they contribute to mucus production and airway protection.^[86] Spatial transcriptomics studies confirm these regional differences, showing distinct transcriptional profiles between proximal airways and distal alveolar compartments.^[87] Epigenetic modifications, particularly DNA methylation, dynamically influence lung gene expression, with environmental factors like smoking inducing lasting changes. Cigarette smoke exposure leads to altered DNA methylation patterns in small airway epithelial cells, repressing or activating genes involved in inflammation and detoxification.^[88] For instance, chronic smoking causes hypermethylation of promoter regions for tumor suppressor genes and hypomethylation of oncogenes, preceding overt lung pathology.^[89] These smoke-induced epigenetic shifts are often reversible upon cessation but can persist in susceptible individuals, affecting overall lung homeostasis.^[90] Single-cell RNA sequencing (scRNA-seq) has revealed cell-type-specific gene expression profiles across lung tissues, highlighting heterogeneity within epithelial and immune compartments. Analyses of human lung samples identify over 50 distinct cell populations, with AT1 cells showing elevated expression of gas exchange facilitators like AGER and PDPN, while AT2 cells upregulate surfactant genes such as SFTPC.^[91] In airway epithelia, goblet cells exhibit high MUC5AC alongside mucin secretion regulators.^[92] These profiles underscore regulatory networks, such as NKX2.1-driven modules in epithelial progenitors, and have mapped variations in healthy versus diseased states.^[93]

Protein Involvement

Pulmonary surfactant proteins B (SP-B) and C (SP-C) are hydrophobic polypeptides integral to the biophysical properties of lung surfactant, a lipid-protein complex that reduces surface tension at the air-liquid interface in alveoli. SP-B plays a critical role in organizing surfactant lipids by promoting the formation of bilayer reservoirs from monolayers and facilitating lipid transfer between the subphase and the air-liquid interface during respiratory cycles. This activity ensures the stability and rapid reformation of surfactant films, preventing alveolar collapse. Similarly, SP-C enhances lipid organization by counteracting the disruptive effects of cholesterol on phospholipid packing, thereby modulating the gel-to-liquid crystalline phase transition and promoting efficient adsorption of surfactant to the alveolar surface. These proteins, encoded by the SFTPB and SFTPC genes respectively, work synergistically to maintain surfactant functionality. Aquaporin-5 (AQP5), a member of the aquaporin family of water channel proteins, is predominantly expressed in alveolar type I epithelial cells and contributes to fluid homeostasis in the lung. It facilitates the rapid, osmotically driven movement of water across cell membranes, enabling efficient clearance of alveolar fluid and regulation of the thin fluid layer essential for gas exchange. By providing a transcellular pathway for water transport, AQP5 helps maintain the delicate balance of hydration in the airspaces without compromising barrier integrity.^[84] The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette transporter functioning as a cAMP-regulated chloride channel in airway and alveolar epithelial cells. It mediates chloride ion efflux across the apical membrane, which drives sodium and water secretion to hydrate the airway surface liquid layer, thereby supporting mucociliary clearance and preventing dehydration of the epithelial lining. CFTR's activity coordinates electrolyte transport to sustain appropriate fluid volumes on mucosal surfaces. Elastin and collagen form the primary fibrous scaffold of the lung's extracellular matrix, dictating its mechanical behavior. Elastin, a highly cross-linked protein, imparts elastic recoil to the parenchyma, allowing the lung to expand during inhalation and return to its resting state upon exhalation with minimal energy loss. Collagen, in contrast, provides tensile strength and resistance to overextension, ensuring structural stability under cyclic loading. Together, these proteins enable the lung's compliance and resilience, with elastin comprising about 2-4% of the dry weight of lung tissue. Cytochrome P450 (CYP) enzymes, a superfamily of heme-containing monooxygenases, are expressed in various lung cell types including Clara cells, type II pneumocytes, and alveolar macrophages. They catalyze the phase I oxidation of xenobiotics such as environmental toxins and drugs, introducing reactive groups that facilitate subsequent conjugation and excretion. This metabolic activity primarily occurs in the bronchial and bronchiolar epithelium, protecting the lung from chemical injury by detoxifying inhaled substances.

Clinical Significance

Inflammatory and Infectious Conditions

Inflammatory and infectious conditions of the lung encompass a range of disorders characterized by immune-mediated responses to pathogens or injury, leading to alveolar damage, impaired gas exchange, and potential respiratory failure. These conditions arise from bacterial, viral, fungal, or mycobacterial invasions that trigger localized or systemic inflammation, often involving cytokine release and recruitment of immune cells such as neutrophils and macrophages. While the lung's protective mechanisms, including mucociliary clearance and alveolar macrophages, initially contain infections, overwhelming responses can exacerbate tissue injury.^[94] Pneumonia, an acute infection of the lung parenchyma, manifests in various forms depending on the causative agent. Bacterial pneumonia, commonly caused by Streptococcus pneumoniae, involves bacterial colonization of the lower respiratory tract following aspiration or inhalation, leading to intense neutrophilic inflammation, alveolar consolidation, and cytokine-mediated damage to epithelial cells.^[95] Viral pneumonia, exemplified by influenza virus infection, primarily targets airway epithelial cells, inducing apoptosis and necrosis while dysregulating cytokine and chemokine production, which compromises the epithelial barrier and facilitates secondary bacterial superinfection.^[96] Fungal pneumonia, such as that induced by Aspergillus species, typically occurs in immunocompromised hosts where inhaled conidia germinate into hyphae, invading lung tissue and eliciting a hypersensitivity response with eosinophilic infiltration and granulomatous inflammation.^[97] Acute respiratory distress syndrome (ARDS) represents a severe inflammatory sequela often triggered by sepsis or trauma, where systemic infection or injury initiates a cytokine storm involving pro-inflammatory mediators like IL-6 and TNF-α, causing diffuse alveolar damage, increased vascular permeability, and protein-rich pulmonary edema.^[98] In sepsis-related ARDS, endothelial and epithelial injury from excessive cytokine release impairs surfactant function and promotes hyaline membrane formation, contributing to hypoxemia and ventilator dependence.^[99] Tuberculosis, caused by Mycobacterium tuberculosis, features a chronic granulomatous pathology where inhaled bacilli are phagocytosed by alveolar macrophages, evading lysosomal killing through inhibition of phagosome maturation and inducing granuloma formation as a host containment strategy.^[100] Granulomas consist of fused macrophages forming multinucleated giant cells, surrounded by lymphocytes and fibroblasts that deposit collagen to wall off the infection, though central caseous necrosis can occur, harboring persistent bacteria and risking dissemination.^[100] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection profoundly affects the lungs, with acute phases showing bilateral ground-glass opacities on imaging due to interstitial inflammation and alveolar exudate from viral replication in type II pneumocytes.^[101] Post-acute sequelae, known as long COVID, include persistent pulmonary fibrosis in up to 30% of hospitalized patients, characterized by reticular patterns and traction bronchiectasis resulting from dysregulated wound healing and fibroblast activation even one year post-infection.^[102] Host-pathogen interactions in lung infections often involve viral hijacking of entry receptors, such as SARS-CoV-2 binding to angiotensin-converting enzyme 2 (ACE2) on alveolar epithelial cells, which facilitates membrane fusion and viral internalization while downregulating ACE2 expression, exacerbating inflammation and endothelial dysfunction.^[103] In bacterial and fungal contexts, pathogens like S. pneumoniae and Aspergillus manipulate immune signaling to promote persistence, such as by inhibiting complement activation or inducing immunosuppressive cytokines.^[95]^[97]

Vascular and Obstructive Disorders

Vascular and obstructive disorders of the lung encompass conditions that impair blood flow through the pulmonary vasculature or obstruct airflow in the airways, leading to significant respiratory compromise. These disorders often result in ventilation-perfusion (V/Q) mismatches, where areas of the lung are ventilated but not adequately perfused, or vice versa, contributing to hypoxemia and increased respiratory effort.^[104] Pulmonary embolism (PE) is a critical vascular disorder characterized by the sudden blockage of a pulmonary artery, typically by a blood clot that originates from deep vein thrombosis (DVT) in the lower extremities. This obstruction disrupts blood flow to the affected lung segments, creating a V/Q mismatch that impairs gas exchange and can lead to acute right heart strain. Symptoms often include sudden dyspnea, pleuritic chest pain, and cough, with severe cases progressing to hemodynamic instability.^[105]^[106] Chronic obstructive pulmonary disease (COPD) represents a major obstructive disorder, encompassing emphysema and chronic bronchitis, both of which progressively limit airflow and cause chronic respiratory symptoms. Emphysema involves the irreversible destruction of alveolar walls, reducing the surface area for gas exchange and leading to air trapping and hyperinflation. Chronic bronchitis, in contrast, features persistent inflammation of the bronchial tubes with excessive mucus production and hypersecretion, resulting in productive cough and recurrent infections. Smoking is the primary risk factor for COPD, accelerating the annual decline in forced expiratory volume in 1 second (FEV1) to approximately 50-70 mL per year in affected individuals, compared to about 30 mL per year in nonsmokers.^[107]^[108]^[109]^[110] Asthma is an obstructive lung disorder marked by reversible bronchoconstriction and airway hyperresponsiveness, primarily driven by IgE-mediated type 2 inflammation. This inflammatory cascade involves the release of mediators from mast cells and eosinophils upon allergen exposure, causing smooth muscle contraction, mucosal edema, and mucus hypersecretion, which narrow the airways and provoke episodic wheezing, shortness of breath, and chest tightness. Unlike COPD, the airflow limitation in asthma is typically reversible with bronchodilators, though chronic inflammation can lead to remodeling if uncontrolled.^[111]^[112] Pulmonary hypertension is a vascular condition defined by persistently elevated pressure in the pulmonary arteries, often exceeding 20 mmHg at rest as measured by right heart catheterization. This increased pressure arises from vascular remodeling, vasoconstriction, and thrombosis in situ, imposing a progressive afterload on the right ventricle and leading to right heart strain, dilation, and eventual failure. Common symptoms include progressive dyspnea, fatigue, and signs of cor pulmonale, with the disorder frequently complicating other lung diseases.^[113]^[114]

Restrictive and Neoplastic Diseases

Restrictive lung diseases encompass a group of disorders that impair lung expansion due to parenchymal stiffness or fibrosis, leading to reduced vital capacity and gas exchange efficiency. These conditions often present with dyspnea, dry cough, and progressive respiratory failure, distinguished from obstructive diseases by preserved airflow but diminished lung volumes on spirometry. Idiopathic pulmonary fibrosis (IPF) represents a prototype of progressive restrictive lung disease, characterized by relentless scarring and thickening of the lung interstitium without identifiable cause. This fibrosis disrupts normal architecture, culminating in honeycombing and honeycomb cysts on high-resolution CT imaging. The median survival following diagnosis is 3–5 years, underscoring the disease's poor prognosis despite antifibrotic therapies like nintedanib and pirfenidone that modestly slow decline.^[115]^[116] Sarcoidosis, another key restrictive entity, involves multisystem non-caseating granulomatous inflammation, with the lungs affected in over 90% of patients, often manifesting as bilateral hilar lymphadenopathy and interstitial infiltrates. These granulomas, composed of epithelioid histiocytes and multinucleated giant cells, can lead to fibrosis in chronic cases, restricting lung compliance and occasionally causing pulmonary hypertension. Diagnosis typically relies on compatible clinical-radiographic findings, biopsy confirmation, and exclusion of mimics like tuberculosis.^[117]^[118] Occupational exposures contribute significantly to restrictive fibrosis, as seen in asbestosis and silicosis. Asbestosis arises from prolonged inhalation of asbestos fibers in industries like shipbuilding and construction, inducing interstitial fibrosis with pleural plaques and a restrictive ventilatory defect; latency periods exceed 20 years, and it synergizes with smoking to elevate lung cancer risk. Silicosis, linked to silica dust in mining and sandblasting, similarly promotes nodular fibrosis and upper lobe predilection, classified into chronic, accelerated, or acute forms based on exposure duration and intensity. Both are preventable through dust control and respiratory protection, yet persist as public health concerns in developing regions.^[119]^[120]^[121] Neoplastic diseases of the lung, particularly primary malignancies, impose restrictive effects through mass lesions, atelectasis, and secondary fibrosis, profoundly impacting respiratory mechanics. Lung cancer is stratified into non-small cell lung cancer (NSCLC), comprising about 85% of cases and including subtypes like adenocarcinoma—the most prevalent histology, often peripheral and linked to KRAS or EGFR mutations—and small cell lung cancer (SCLC), accounting for roughly 15% and notorious for rapid growth, early metastasis, and paraneoplastic syndromes due to its neuroendocrine origin. Adenocarcinoma frequently arises in non-smokers and women, while SCLC is strongly tied to heavy tobacco use and exhibits extreme chemosensitivity initially but high relapse rates.^[122]^[123]^[124] Advancements in targeted therapies have transformed management of mutation-driven lung cancers, particularly EGFR inhibitors for NSCLC harboring EGFR alterations, present in 10–15% of Western patients and up to 50% in Asian cohorts. These oral tyrosine kinase inhibitors block EGFR signaling, improving progression-free survival over chemotherapy. Notable 2020s developments include the 2020 FDA approval of ramucirumab plus erlotinib combination for first-line EGFR exon 19 deletion or exon 21 L858R mutant metastatic NSCLC, enhancing overall survival in refractory settings. In 2020, osimertinib gained adjuvant approval post-resection for early-stage EGFR-mutated NSCLC, reducing recurrence risk by 80%. More recently, in 2025, sunvozertinib received accelerated FDA approval for pretreated metastatic NSCLC with EGFR exon 20 insertion mutations, addressing a historically underserved subtype with objective response rates around 50%. In June 2025, taletrectinib received FDA approval for locally advanced or metastatic ROS1-positive NSCLC. In October 2025, lurbinectedin in combination with atezolizumab was approved as first-line maintenance therapy for extensive-stage SCLC.^[125]^[126]^[127]^[128]^[129]

Congenital Anomalies

Congenital anomalies of the lung encompass a range of structural birth defects that arise during embryonic development, often leading to impaired respiratory function and requiring early intervention. These malformations can involve abnormal partitioning of the thoracic cavity, aberrant lung tissue formation, or disrupted vascular and bronchial connections, with varying degrees of severity depending on the extent of pulmonary hypoplasia or associated complications.^[130] One of the most significant congenital lung anomalies is congenital diaphragmatic hernia (CDH), in which a defect in the diaphragm allows abdominal organs such as the intestines or stomach to herniate into the thoracic cavity, compressing the developing lungs and resulting in pulmonary hypoplasia. This condition occurs in approximately 1 in 2,500 live births and is characterized by underdeveloped lung tissue on the affected side, often accompanied by pulmonary hypertension due to vascular abnormalities.^[130]^[131] The herniation typically occurs through a posterolateral defect known as a Bochdalek hernia, which disrupts normal lung growth during the pseudoglandular stage of embryogenesis.^[130] Tracheoesophageal fistula (TEF) represents another critical anomaly, defined as an abnormal epithelial-lined connection between the trachea and esophagus, frequently occurring in conjunction with esophageal atresia where the esophagus fails to develop as a continuous tube. This malformation affects about 1 in 3,500 live births and arises from incomplete separation of the tracheoesophageal septum during foregut development around the fourth week of gestation.^[132]^[133]^[134] The most common type (85% of cases) involves a proximal blind-ending esophagus and a distal fistula connecting the trachea to the lower esophagus, leading to risks of aspiration, choking, and respiratory distress in newborns.^[133] Pulmonary sequestration is a rare congenital malformation consisting of non-functioning dysplastic lung tissue that lacks normal communication with the tracheobronchial tree and receives its arterial blood supply from anomalous systemic vessels, typically from the aorta. These sequestered segments, which can be intralobar (within a normal lobe) or extralobar (separate from the lung), often present as recurrent infections or hemoptysis if undiagnosed until later in life, though they may be asymptomatic at birth.^[135] The condition results from an error in lung bud formation during early embryogenesis, leading to isolated tissue that functions more like a mass than viable pulmonary parenchyma.^[136] Congenital pulmonary airway malformation (CPAM), formerly known as congenital cystic adenomatoid malformation, involves the formation of cystic masses within the lung parenchyma due to excessive proliferation of terminal bronchiolar structures, creating fluid-filled cysts that impair normal gas exchange. These lesions are classified into types based on cyst size and histology, with type I featuring large cysts greater than 2 cm in diameter, type II with smaller uniform cysts (0.5-1.2 cm), and type III presenting as solid microcystic areas.^[137] CPAMs account for about 25% of congenital lung malformations and can cause respiratory distress if large, though many are detected prenatally via ultrasound.^[138] Certain genetic syndromes are associated with congenital lung underdevelopment, such as Fryns syndrome, an autosomal recessive disorder caused by biallelic variants in genes like PIGN, leading to pulmonary hypoplasia alongside diaphragmatic defects and other multiorgan anomalies. Fryns syndrome exemplifies how genetic disruptions in developmental pathways can result in severe lung immaturity, often manifesting as small, underdeveloped lungs that contribute to neonatal respiratory failure.^[139]^[140] These genetic links highlight the role of mutations in foregut and mesenchymal signaling in the etiology of lung anomalies, with Fryns syndrome occurring sporadically due to its rarity.^[141]

Diagnostic Approaches

Diagnostic approaches to the lung encompass a range of non-invasive and invasive techniques designed to assess pulmonary structure, function, and potential abnormalities. These methods allow clinicians to evaluate lung parenchyma, airways, vasculature, and pleural spaces, often beginning with imaging for anatomical overview and progressing to functional tests or direct visualization as needed. Selection of approaches depends on clinical suspicion, with the goal of providing precise, quantifiable data to guide further management. Imaging modalities form the cornerstone of initial lung evaluation, offering visualization of gross anatomy such as lobes and segments. Chest X-ray serves as the first-line tool, delivering posteroanterior or anteroposterior projections to detect basic abnormalities like airspace opacities or pleural effusions with minimal radiation exposure.^[142] Computed tomography (CT), particularly multidetector CT, provides detailed cross-sectional images of lung lobes and segments, enabling assessment of nodules, infections, and interstitial changes through thin-slice acquisitions.^[142] Magnetic resonance imaging (MRI) excels in evaluating vascular flow and soft tissue characteristics without ionizing radiation, using T1-, T2-, and diffusion-weighted sequences to differentiate benign from potentially malignant lesions.^[142] Pulmonary function testing, including spirometry, quantifies airflow and volume to differentiate obstructive from restrictive patterns. In spirometry, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) are measured, with the FEV1/FVC ratio below 0.7 indicating airflow obstruction.^[143] A reduced FVC, when confirmed by total lung capacity below the lower limit of normal, suggests restriction.^[143] These metrics, standardized by the Global Lung Function Initiative, provide a benchmark for interpreting deviations from expected values based on age, height, sex, and ethnicity.^[143] Measurement of pleural space pressure via manometry assesses the dynamics between the lung and chest wall, typically performed during thoracentesis using electronic transducers, digital devices, or water manometers. Normal intrapleural pressure at functional residual capacity ranges from -3 to -5 cmH₂O, becoming more negative (up to -10 cmH₂O) during inspiration to facilitate lung expansion.^[144] This technique monitors pressure changes with fluid removal, with pleural elastance normally between 0.5 and 14.5 cmH₂O/L, helping to identify risks like lung entrapment.^[144] Bronchoscopy enables direct endoscopic examination of the airways, inserted via a flexible fiberoptic scope through the nasal cavity or mouth to visualize the trachea and bronchi up to sub-segmental levels. The procedure allows for real-time assessment of mucosal integrity and airway patency, with integrated tools like forceps for obtaining biopsies to sample tissue for histopathological analysis.^[145] Performed under sedation, it requires post-procedure monitoring for complications such as bleeding or pneumothorax.^[145] Recent advances since 2020 have integrated artificial intelligence (AI) into lung imaging, enhancing early detection capabilities through deep learning models applied to CT scans. For instance, AI algorithms like Google's deep learning system achieve high area under the curve (AUC) values, such as 94.4% on large datasets, by reducing false positives and improving nodule classification for timely intervention.^[146] The Sybil model exemplifies predictive AI, forecasting lung cancer risk from low-dose CT with AUCs up to 0.92 for short-term detection, supporting scalable screening programs.^[146] These tools address challenges like interobserver variability while emphasizing the need for diverse training data to mitigate biases.^[146]

Comparative and Evolutionary Aspects

Lungs in Other Animals

In birds, the lungs are characterized by a parabronchial structure consisting of rigid, tubular parabronchi that facilitate gas exchange through a cross-current mechanism, achieving higher oxygen extraction efficiency than in mammalian lungs (typically 25-35%).^[147]^[148] Unlike mammalian lungs, avian lungs maintain unidirectional airflow through the parabronchi, moving continuously from caudal to cranial directions during both inspiration and expiration, supported by aerodynamic valving at the air sac-lung interface.^[147] This system is complemented by a network of nine flexible air sacs—cervical, thoracic, and abdominal—that act as bellows to store and propel air, with compliances around 191.5–258.5 mL/cmH₂O and ventilation volumes of 16.3–21.5 mL per breath per side.^[147] Birds lack a diaphragm, relying instead on synchronized movements of the ribs, sternum, and body wall muscles to alter coelomic pressure for ventilation.^[147] Reptilian lungs exhibit a sac-like morphology with incomplete septa forming internal chambers, varying in complexity from simple low septa in tuataras and snakes to more partitioned structures in lizards, turtles, and crocodilians.^[149] These septa, often faviform in early reptiles, protrude from the inner walls without forming complete networks, allowing for less efficient but adaptable gas exchange compared to higher vertebrates.^[149] Ventilation mechanisms differ across groups; for instance, crocodilians employ a hepatic pump, where liver movement driven by caudal musculature compresses abdominal air sacs connected to the lungs, facilitating airflow in a manner that hints at the origins of avian unidirectional systems.^[149] Amphibians possess simple sac-like lungs with thick walls and minimal septation, often developing primary alveolar septa lined with smooth muscle only after inflation during metamorphosis, as seen in species like Xenopus laevis where lungs reach 0.5–1 times the pleuroperitoneal cavity length post-inflation.^[150] These lungs supplement rather than dominate respiration, with buccopharyngeal breathing—gas exchange via the mouth and pharyngeal epithelium—playing a primary role, especially in aquatic tadpoles where buccal pumping drives both ventilation and feeding.^[150] In adults, lung inflation is achieved through buccal force pumps, increasing breathing frequency to 30–50 breaths per hour under air exposure, though skin and buccal surfaces remain critical for overall oxygen uptake.^[150] In fish, the swim bladder serves as an ancestral homolog to lungs but functions primarily for buoyancy control rather than gas exchange, evolving from gas-holding structures in early osteichthyans with squamous or cuboidal epithelial linings containing lamellar bodies.^[151] This organ, also called a gas bladder, adjusts fish depth by regulating gas volume via a gas gland that secretes oxygen from the bloodstream, counteracting the density of bone and muscle without direct respiratory involvement in most modern species like teleosts.^[151] While some primitive fish retain accessory respiratory roles, the swim bladder's surfactant system—rich in phosphatidylcholine—supports structural integrity for hydrostatic functions, reflecting convergent evolution across ray-finned and lobe-finned lineages.^[151] Mammalian lungs, excluding humans, feature alveolar structures with thin walls optimized for gas exchange, but adaptations vary; for example, cetaceans exhibit reinforced alveoli with thickened walls and abundant elastic fibers to withstand deep-sea pressures during dives.^[152] In cetaceans like dolphins and whales, these modifications enable complete lung collapse at depths exceeding 100 meters, minimizing nitrogen absorption and decompression sickness risk through high thoracic compliance and low residual volumes.^[152] Pulmonary surfactants in these species are enhanced to reduce surface tension, facilitating rapid re-expansion upon surfacing, with genetic adaptations in 21 rapidly evolving genes such as SFTPC supporting fibrosis-like resilience in alveolar tissues.^[152]

Evolutionary Origins

The evolutionary origins of lungs trace back to the Devonian period, approximately 419–359 million years ago, when early bony fishes (Osteichthyes) developed air-breathing organs to supplement gill-based respiration in oxygen-poor aquatic environments.^[153] These primitive lungs likely arose as dorsal outpocketings of the foregut in the common ancestor of all bony fishes, serving initially as accessory respiratory structures rather than primary buoyancy organs.^[154] In the lineage of sarcopterygians (lobe-finned fishes), which include the ancestors of tetrapods, these structures evolved into functional lungs capable of supporting bimodal breathing, allowing survival in shallow, hypoxic waters.^[155] Contrary to earlier views, swim bladders in ray-finned fishes (Actinopterygii) are considered derived from these ancestral lungs, with a topological inversion from ventral to dorsal positioning during development.^[156] The transition from aquatic to terrestrial life in early tetrapods built upon this sarcopterygian foundation, with air-breathing becoming essential during the Late Devonian as vertebrates ventured onto land.^[153] Living lungfishes (Dipnoi), the closest extant relatives to tetrapods, serve as key models for this transition, retaining simple, vascularized lungs that enable prolonged estivation in mud during droughts, mirroring the adaptive pressures faced by Devonian ancestors.^[157] Fossil evidence from this era, such as the early tetrapod Ichthyostega dated to around 375 million years ago, reveals skeletal adaptations including robust ribs suggestive of lung ventilation mechanics, alongside limb-like fins for shallow-water propulsion.^[158] These primitive lungs were initially unpaired and saccular, facilitating gas exchange through simple diffusion, but lacked the compartmentalization seen in later forms.^[153] While vertebrate lungs represent a unified evolutionary lineage, analogous respiratory structures in invertebrates arose independently much earlier, highlighting convergent adaptations to aerial or low-oxygen environments. Tracheal systems in insects, consisting of branching air-filled tubes that deliver oxygen directly to tissues via diffusion, evolved around 400 million years ago in early arthropods.^[159] Book lungs in arachnids, such as spiders and scorpions, feature stacked, air-filled lamellae for gas exchange and date back to the Silurian period over 420 million years ago.^[160] In mollusks, mantle cavities function as primitive lungs in pulmonate gastropods, where vascularized tissues in the pallial cavity enable aerial respiration, an adaptation that emerged in the Paleozoic era.^[161] Key adaptations in vertebrate lung evolution enhanced efficiency for terrestrial life. Vascularization intensified with the development of a dedicated pulmonary circulation, separating systemic and respiratory blood flows to optimize oxygen uptake, a trait evident in early tetrapods.^[162] In amniotes, which arose in the Carboniferous period around 330 million years ago, the evolution of pulmonary surfactant—a phospholipid-protein complex produced by alveolar cells—prevented lung collapse during exhalation and supported alveolar expansion, marking a critical innovation for fully terrestrial respiration.^[151] These changes, absent in anamniotes like amphibians, underscore the stepwise refinement of lungs from simple air sacs to complex, efficient organs.^[163]

Society and Culture

Culinary Uses

Animal lungs, known as "lights" in butchery, are utilized as offal in various global cuisines, valued for their affordability and contribution to nose-to-tail eating practices.^[164] In Scottish cuisine, lungs form a key ingredient in haggis, where sheep lungs are boiled, finely chopped, and mixed with heart, liver, oatmeal, onions, suet, and spices before being stuffed into a sheep's stomach and simmered.^[165] This traditional dish exemplifies the use of lungs in hearty, spiced preparations. Similarly, in Chinese cuisine, lungs feature in dishes like fuqi feipian ("husband and wife lung slices"), a Sichuan specialty involving thinly sliced beef lungs (though modern versions often substitute tripe or brisket) tossed in chili oil, sesame, and spices for a spicy, cold appetizer.^[166] Stir-fried pork or beef lungs are also common in regional Chinese recipes, quickly wok-tossed with garlic, ginger, and soy sauce to highlight their mild flavor.^[167] Nutritionally, animal lungs are a dense source of protein, providing approximately 17-20 grams per 100 grams, along with B vitamins (particularly B12 and niacin), iron (around 5-8 mg per 100 grams, aiding oxygen transport), and trace minerals like selenium and copper.^[168] However, as respiratory organs, lungs may bioaccumulate heavy metals and pollutants from inhaled air or environmental exposure, potentially leading to elevated levels of contaminants like lead or cadmium in consumed offal, necessitating careful sourcing from clean environments.^[169] Historically, lungs appeared in medieval European sausages, such as 15th-century recipes for lungwurst, where chopped calf or pig lungs were blended with bacon, spices, and blood, then stuffed into casings like the rectum and boiled for preservation.^[170] In Native American traditions, particularly among Plains tribes like the Lakota, dried lungs were consumed as a portable food, sometimes stuffed with jerked meat, herbs, and berries before drying, serving as a nutrient-rich provision for hunts or travels.^[171] In modern contexts, lungs remain popular in Europe and Asia but face restrictions in the United States, where the USDA banned their sale for human consumption in 1971 due to concerns over trapped stomach fluids, blood, and microbial contamination during slaughter, which could pose hygiene risks.^[172] Despite this, lungs are staples in Scottish haggis production and Asian dishes like Indonesian paru goreng (deep-fried beef lungs), where they are widely available and culturally embraced.^[173] Preparation techniques emphasize thorough cleaning to remove residual blood and debris: lungs are typically rinsed under cold water, sometimes soaked in vinegar or milk, then parboiled for 10-20 minutes to expel impurities and reduce any gamey taste.^[173] Due to their fibrous, spongy texture, slow cooking methods—such as simmering in stock with aromatics for 1-2 hours or braising in milk—are preferred to tenderize the tissue, followed by slicing, frying, or incorporating into stews for optimal palatability.^[174]

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Physical adaptation of children to life at high altitude
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Physiological and Genetic Adaptations to Diving in Sea Nomads
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The lungs are composed of branching airways that terminate in respiratory bronchioles and alveoli, which participate in gas exchange. Most bronchioles and large ...Cellular Level · Organ Systems Involved · Clinical Significance<|control11|><|separator|>
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Partial Pressure of Oxygen - StatPearls - NCBI Bookshelf - NIH
While PAO2 is the partial pressure of oxygen in the alveoli, Patm is the atmospheric pressure at sea level equaling 760 mm Hg. PH2O is the partial pressure ...Missing: PCO2 | Show results with:PCO2
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If alveolar ventilation is 4 L/min and pulmonary blood flow is 5 L/min, then the V̇/Q̇ ratio equals 0.8. If ventilation and perfusion of all alveoli were the same ...
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Ventilation/Perfusion Relationships and Gas Exchange
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By modifying hemoglobin oxygen affinity, carbon dioxide also facilitates respiratory gas exchange in the lungs. At the lungs, carbon dioxide is given up by ...
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Three classical papers in respiratory physiology by Christian Bohr ...
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May 1, 2023 · Alveolar tension is a collapsing force that plays a crucial role in maintaining this balance.Introduction · Structure · Function · Pathophysiology
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The Role of Surfactant in Lung Disease and Host Defense against ...
Pulmonary surfactant is essential for life as it lines the alveoli to lower surface tension, thereby preventing atelectasis during breathing.
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21.6A: Factors Affecting Pulmonary Ventilation: Surface Tension of ...
Oct 14, 2025 · The surfactant reduces surface tension within all alveoli through hydrophilic and hydrophobic forces. Insufficient pulmonary surfactant in the ...
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Mucociliary clearance (MCC) is the primary innate defense mechanism of the lung. The functional components are the protective mucous layer, the airway ...
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Alveolar macrophages in pulmonary host defence - NIH
Macrophages are key orchestrators of inflammatory responses in the lung. They produce key regulatory cytokines, such as IL-1β, which helps to prime release of ...Alveolar Macrophages Role In... · Fig. 2 · Apoptosis-Associated Killing
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Alveolar macrophages in tissue homeostasis, inflammation, and ...
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The cough reflex protects the airways and lungs from aspiration, inhaled irritants, particulates and pathogens and clears the air spaces of accumulated ...
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The sneeze reflex in physiological and pathological states
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The pulmonary collectins, SP-A and SP-D, orchestrate innate ... - NIH
The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung · Lung-specific requirements for host defense · Surfactant proteins and pulmonary ...Missing: immunoglobulin | Show results with:immunoglobulin
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SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral ...
Surfactant proteins A (SP-A) and D (SP-D) are soluble innate immune molecules which maintain lung homeostasis through their dual roles as anti-infectious ...
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Here we found that an acidic pH impairs the ability of two key airway antimicrobial peptides, β-defensin-3 and LL-37, to kill bacteria.
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Angiotensin-converting enzyme 2 in lung diseases - PMC
Abstract. The renin-angiotensin system (RAS) plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance.
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Pulmonary Capillary Endothelium-Bound Angiotensin-Converting ...
Background—Pulmonary endothelium has metabolic functions including the conversion of angiotensin I to angiotensin II by angiotensin-converting ectoenzyme ...
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ACE Inhibitors - StatPearls - NCBI Bookshelf - NIH
May 4, 2025 · The Angiotensin converting enzyme (ACE) inhibitors are a class of medication used to treat and manage hypertension, a significant risk factor ...
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Prostaglandin and leukotriene production by alveolar type II cells in ...
We conclude that primary cultures of alveolar type II cells are capable of the de novo metabolism of arachidonic acid to both cyclooxygenase and lipoxygenase ...
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The Role of Prostaglandins in Allergic Lung Inflammation and Asthma
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Pulmonary pathways and mechanisms regulating transpulmonary ...
Because increased bubble density represents a greater breach in the pulmonary capillary filter ... lung filters out blood clots. Our previous work has clearly ...
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Iatrogenic air embolism: pathoanatomy, thromboinflammation ...
Bubbles can cross the pulmonary capillary bed and enter arterial circulation if they overwhelm pulmonary filtration capacity (64).
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Brainstem control of vocalization and its coordination with respiration
Phonation process dominantly occurs during expiration: narrowing of the larynx (vocal cord adduction) while simultaneously exhaling air (3). In general, ...
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Physiology, Acid Base Balance - StatPearls - NCBI Bookshelf - NIH
This is why a reduced respiratory rate leads to a decreased pH; the more carbon dioxide is exhaled, the less carbon dioxide is present for this reaction.
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FOXF1 Transcription Factor Promotes Lung Morphogenesis by ... - NIH
FOXF1 promotes lung morphogenesis by regulating mesenchymal-epithelial signaling and stimulating cellular proliferation in fetal lung mesenchyme.
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Genetic and Cellular Mechanisms in Lung Development - PMC - NIH
In contrast, vitamin A deficiency impairs lung epithelial function in rodents and causes bronchopulmonary dysplasia in humans (Biesalski and Nohr, 2003; Verma ...
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Lung Endoderm Morphogenesis: Gasping for Form and Function - NIH
Prior to this proximal-distal patterning, the lung endoderm broadly expresses several transcriptional regulators, including Nkx2.1, Gata6, and Foxa1/2 (Figure 3) ...
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The genes SFTPA1, SFTPA2, SFTPB, SFTPC and SFTPD encode the apolipoproteins that form approximately 8% of the surfactant fluid (consisting of surfactant ...
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Differential Regulation of Human Surfactant Protein A Genes ...
The SFTPA1 and SFTPA2 genes encode proteins that contain both collagenous and carbohydrate regions (22, 30) that places them in the family collagenous C-type ...
[80]
178620 - SURFACTANT, PULMONARY-ASSOCIATED PROTEIN C ...
It is produced exclusively by type II alveolar epithelial cells in the lung. Pulmonary surfactant is a lipid-rich material that prevents lung collapse by ...Missing: SFTPA | Show results with:SFTPA<|separator|>
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Apr 8, 2018 · One distinguishing feature of AT1 cells is the high level of expression of the gene Ager, encoding the advanced glycation endproduct–specific ...
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Identification of lung‐specific genes by meta‐analysis of multiple ...
The SFTP gene family, which encodes lung surfactant proteins, was represented by expression of five genes (SFTPA1, SFTPA2, SFTPC, SFTPB, and SFTPD) in at least ...
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Control of lung defence by mucins and macrophages
MUC5AC is found predominantly in surface epithelia throughout the central conducting airways, whereas MUC5B is found mainly in submucosal glands of central ...
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Cigarette smoking induces small airway epithelial epigenetic ...
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Chronic Cigarette Smoke-Induced Epigenomic Changes Precede ...
The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months.
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The role of cigarette smoke-induced epigenetic alterations in ...
Nov 11, 2019 · DNA methylation altered by tobacco smoke is a reversible gene regulatory modification. After smoking cessation, the majority of the ...
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A molecular cell atlas of the human lung from single-cell RNA ...
Oct 18, 2024 · We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously ...
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Cell-type-specific and disease-associated expression quantitative ...
Mar 28, 2024 · In this study, we present a characterization of regulatory genetic variants across major cell types in the human lung, using scRNA-seq to ...
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Single-cell multiomic profiling of human lungs reveals cell-type ...
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Bacterial pneumonia, characterized by inflammation in lung parenchyma and alveolar spaces, is caused by various bacteria, each triggering an intricate interplay ...Bacterial Pneumonia · Pathophysiology · History And Physical
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Streptococcus pneumoniae - StatPearls - NCBI Bookshelf - NIH
The severity of the pneumococcal disease is due to significant inflammatory response induced by the activation of complement pathways and cytokine release by ...
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Potential mechanisms include dysregulation of cytokines and chemokines, infection of epithelial cells in the lungs, and apoptosis. Virus has a pathogenic effect ...
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Aspergillosis - StatPearls - NCBI Bookshelf
Feb 22, 2023 · Aspergillosis is a spectrum of infections caused by fungi from the Aspergillus genus. The species most involved include A. fumigatus, A. terreus, A. flavus, ...
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This article presents an exhaustive review that highlights the previously unrecognized relationship between sepsis and ARDS and suggests a direction for future ...
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Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome that manifests secondary to numerous etiologic insults, and consequently it ...
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Apr 24, 2025 · The most common CT findings included ground-glass opacities, reticular patterns, and traction bronchiectasis, particularly increasing with age ...
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Sep 24, 2025 · Pulmonary fibrosis. One potential cause of long-term pulmonary symptoms in COVID-19 recovery patients is pulmonary fibrosis (Figure 1).
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SARS-CoV-2 entry into the host is mediated by binding of viral spike protein to the Human angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is an essential ...
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Symptoms of PE vary and are often nonspecific, including dyspnea, chest pain, cough, and syncope. Severe cases may involve hemodynamic instability and signs of ...
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Nov 8, 2024 · COPD is a lung disease that makes it hard to breathe. It includes emphysema and chronic bronchitis. COPD is a major cause of disability and ...Symptoms · COPD - Diagnosis · Causes and Risk Factors · COPD - Treatment
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Jun 24, 2023 · Since there are two phases of asthma, it is essential to try to target and decrease bronchoconstriction, inflammation, and airway remodeling.
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Apr 17, 2021 · Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disorder with an estimated median survival time of 3–5 years after diagnosis.
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Pulmonary edema. Connective tissue diseases. Go to: Prognosis. IPF is a progressive disorder with a median survival time of around 5 years. However, about 20 ...
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Asbestosis and silicosis are chronic non-malignant lung diseases caused by inhalation of hazardous dusts found in a variety of workplaces.
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SCLC comprises about 15% of lung cancer while NSCLC comprises approximately 85%. ... Combined SCLC is defined as SCLC with non-small cell components such as ...
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Congenital diaphragmatic hernia is a condition resulting from the herniation of abdominal contents into the thoracic cavity resulting in lung hypoplasia and ...Etiology · Pathophysiology · Evaluation · Treatment / Management
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Jul 2, 2024 · Esophageal atresia is a related congenital malformation with a similar presentation to TEF and can occur with or without a fistula.
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Intralobar sequestration is characterized by aberrant formation of nonfunctional lung tissue that has no communication with the bronchial tree.
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The Origin and Evolution of the Surfactant System in Fish
Lungs and swim bladders have different ontogenetic origins and can be used either for buoyancy or as an accessory respiratory organ.
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Evolutionary genetics of pulmonary anatomical adaptations in deep ...
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Lungs and swim bladders have different ontogenetic origins and can be used either for buoyancy or as an accessory respiratory organ.Missing: ancestral | Show results with:ancestral
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We're more like primitive fishes than once believed
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Lungs of the first amniotes: why simple if they can be complex?
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What's So 'Offal' About Haggis and Why's It Banned in the U.S.?
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Husband and Wife Lung Slices (or Brisket and Tripe) Recipe
Rating 5.0 (1) · 3 hr 30 minThe name of the dish in Chinese, Fu Qi Fei Pian, means "Husband and Wife Lung Slices." Though the dish is traditionally made with lungs.
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Sichuan Fuqi Feipian (夫妻肺片) - The Woks of Life
Rating 5.0 (14) · 5 hr 30 minMar 9, 2022 · Fuqi feipian (夫妻肺片; fūqī fèipiàn) is about as Sichuan as it gets. It's a dish of sliced beef and tripe, swimming in chili oil with that ...Missing: stir- | Show results with:stir-
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Health Risk Assessment of Exposure to Heavy Metals from Sheep ...
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Lung Sausage after Rheinfränkisches Kochbuch - culina vetus
Nov 21, 2021 · Take the rectum of a calf and make it very clean. Chop lungs and bacon together, season it well and rub it in, and put that into the rectum.
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Guts and Grease: The Diet of Native Americans
Modern man has lost his taste for the kinds of foods the Indians ate—how many American children will eat raw liver, dried lung or sour porridge? How then ...
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Paru Goreng: Deep Fried Beef Lungs - Cook Me Indonesian
2 hrDec 1, 2020 · Instructions · Clean the beef lung thoroughly using running water. · Place the meat in a cooking pan, cover it with water and boil for 10 minutes.<|separator|>
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Cooking Lungs: Nose to Tail Eating - Practical Self Reliance
Aug 5, 2021 · “Salt and pepper pieces of lungs and fry them in butter until well browned. Sprinkle with flour, stir well, and cook for a few minutes more (or ...