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Respiratory epithelium

The respiratory epithelium is a specialized layer of cells that lines the conducting and respiratory portions of the respiratory tract, from the nasal cavity to the alveoli, serving as a dynamic barrier that protects against pathogens, particulates, and environmental insults while facilitating air conduction and gas exchange.^[1] Primarily composed of ciliated pseudostratified columnar epithelium in the upper airways, it transitions to simple squamous epithelium in the alveoli to optimize diffusion of oxygen and carbon dioxide.^[2] In the conducting airways, such as the trachea and bronchi, the epithelium consists of multiple cell types, including ciliated columnar cells that bear motile cilia for propulsion, goblet cells that secrete mucus to trap debris, basal cells that act as stem cells for regeneration, and occasional club and neuroendocrine cells.^[1] These cells rest on a distinct basement membrane, with the pseudostratified appearance arising from nuclei at varying heights despite all cells contacting the basement membrane; in the trachea, this membrane is notably thick.^[2] Further down the tract, in bronchioles, the epithelium shifts to simple cuboidal, lacking goblet cells and cartilage, while the alveoli feature type I pneumocytes (thin squamous cells for gas exchange) and type II pneumocytes (cuboidal cells that produce surfactant to reduce surface tension).^[3] The primary functions of the respiratory epithelium extend beyond physical protection to include mucociliary clearance, where cilia beat at 8-20 Hz to propel mucus-trapped particles upward toward the pharynx, alongside humidification and warming of inhaled air.^[1] In the alveoli, it enables efficient gas exchange through its thin structure, while type II cells also contribute to innate immunity by secreting antimicrobial peptides.^[2] Additionally, epithelial cells play active roles in immune modulation by recognizing pathogens via pattern recognition receptors like Toll-like receptors, secreting cytokines such as IL-6 and IL-8 to recruit immune cells, and influencing airway remodeling in response to infections or inflammation.^[3]

Anatomy and Structure

Location and Regional Variations

The respiratory epithelium lines the conducting portion of the respiratory tract, extending from the nasal cavity through the trachea, bronchi, and bronchioles to the terminal bronchioles, where it transitions to the simple squamous epithelium of the alveoli specialized for gas exchange.^[1] This mucosal lining serves as the interface between the external environment and the internal milieu, adapting structurally to varying airflow dynamics and exposures along the tract.^[4] In the upper respiratory tract, including the nasal passages, nasopharynx, trachea, and larger bronchi, the epithelium is predominantly pseudostratified ciliated columnar, appearing multilayered due to nuclei at different heights within a single cell layer, which provides robust protection against inhaled particles and pathogens.^[2] As the airways branch into smaller bronchi and bronchioles, the epithelium transitions to simple cuboidal, with reduced height and fewer cilia to accommodate smoother airflow in narrower passages; in terminal bronchioles, it becomes simple columnar or cuboidal, further thinning to facilitate the shift toward gas exchange in adjacent respiratory zones.^[5] These layering differences—thicker and more stratified proximally for barrier reinforcement, versus progressively simpler and thinner distally—optimize protection in high-exposure regions while minimizing diffusion barriers in lower airways.^[1] The total surface area of the respiratory epithelium in the conducting airways of an adult human lung is approximately 0.25 m², a relatively small fraction compared to the 70–100 m² of the alveolar surface area dedicated to gas exchange.^[6] Histological adaptations reflect regional environmental demands, with goblet cells—responsible for mucus production—being more abundant in proximal airways like the trachea and bronchi due to greater particulate matter exposure, decreasing markedly in distal bronchioles.^[7] This proximal enrichment enhances trapping and clearance in areas of highest contaminant load.^[4]

Cellular Composition

The respiratory epithelium in the proximal conducting airways is a pseudostratified columnar structure composed of multiple cell types that vary in abundance and morphology along the airway tract. Primary cell types include ciliated cells, goblet cells, and basal cells, which together account for the majority of epithelial cells in the conducting airways.^[1] Ciliated cells predominate, comprising 50-80% of the epithelial population in the upper airways, and are characterized by their tall, columnar shape and apical surface covered by 200-300 motile cilia arranged in a 9+2 microtubule pattern, visible under electron microscopy.^[1]^[8] Goblet cells, making up 5-25% of cells in proximal airways, are mucus-secreting columnar cells filled with apical mucin granules that stain positively with periodic acid-Schiff, contributing to the epithelial's secretory component.^[1] Basal cells form a layer at the base of the epithelium, representing 6-30% of total cells depending on airway generation, and exhibit a cuboidal morphology with hemidesmosomal attachments to the basement membrane, serving as anchors and possessing stem-like properties.^[9]^[8] Rare and specialized cell types constitute less than 5% of the epithelium but play distinct roles in secretion, sensation, and ion regulation. Club cells, also known as Clara cells, are non-ciliated, dome-shaped cuboidal cells prominent in terminal bronchioles, where they can reach up to 20% abundance, and feature prominent rough endoplasmic reticulum for serous secretion.^[1]^[10] Neuroendocrine cells are solitary or clustered (as neuroepithelial bodies), innervated, and contain dense-core granules that store peptides such as serotonin, occurring at frequencies below 1% throughout the airways.^[10] Brush cells, rare tuft-like cells with extensive apical microvilli, are equipped for chemosensory functions and represent under 1% of the population.^[8] Ionocytes, a recently identified rare subtype (approximately 0.45% of airway cells), are small cells expressing high levels of CFTR and FOXI1, specialized for ion transport, with single-cell studies revealing their heterogeneity across airway regions.^[11] Cell proportions shift regionally, with the trachea featuring higher densities of ciliated (around 60%) and goblet cells compared to distal bronchioles, where club cells increase to 15-20% and basal cells decrease.^[8]^[10] At the ultrastructural level, epithelial integrity is maintained by tight junctions (zonula occludens), which form apical seals between cells to prevent paracellular leakage, and desmosomes, which provide adhesion via cadherin-mediated links, both observable via transmission electron microscopy.^[1]^[12] Advances in single-cell RNA sequencing have expanded the known diversity, identifying over 10 epithelial subtypes in human airways, including multiciliated variants, transitional secretory states, and ionocyte subpopulations with distinct transcriptional profiles.^[13] For instance, a 2025 atlas of the upper respiratory epithelium delineated 18 cell types, highlighting ionocyte heterogeneity linked to CFTR expression gradients.^[14]^[11] These findings underscore the epithelium's cellular complexity beyond classical classifications.^[8]

Development and Regeneration

Embryonic Origins

The respiratory epithelium originates from the endoderm during the fourth week of gestation, when a ventral outgrowth from the foregut forms the lung primordium, or respiratory diverticulum, which bifurcates into left and right primary bronchial buds.^[15] This initial budding establishes the foundational epithelial lining of the trachea and main bronchi, separating from the foregut via the tracheoesophageal septum.^[16] Lung development proceeds through distinct stages that shape the respiratory epithelium. In the pseudoglandular stage (weeks 5-17), extensive branching morphogenesis occurs, generating the conducting airway tree with an initial epithelial lining of columnar cells.^[17] The canalicular stage (weeks 16-26) involves further subdivision into respiratory bronchioles, vascularization, and early differentiation of epithelial cells, including the emergence of type I and type II pneumocytes.^[16] During the saccular stage (weeks 24-38), primitive alveoli form as terminal sacs lined by flattened type I cells for gas exchange and cuboidal type II cells that produce surfactant precursors.^[15] The alveolar stage begins postnatally and traditionally continues until approximately 3-8 years of age, though recent evidence suggests alveolarization may extend into adolescence or early adulthood through continued septation. This extended process involves microvascular maturation and septal remodeling, with implications for catch-up growth in preterm infants.^[18]^[19]^[20] Key signaling pathways orchestrate these processes. Fibroblast growth factor 10 (FGF10) drives branching morphogenesis by promoting epithelial proliferation from mesenchymal sources.^[21] Sonic hedgehog (SHH) signaling patterns the proximal-distal axis and regulates mesenchymal growth.^[22] Wnt and bone morphogenetic protein (BMP) pathways specify proximal (e.g., via Sox2 expression in conducting airways) versus distal epithelial fates.^[23] Sox2 maintains proximal epithelial identity and progenitor potential.^[24] Epithelial differentiation includes the appearance of basal cells around weeks 9-12 post-conception, serving as progenitors in proximal airways.^[25] Ciliated cells emerge by approximately week 11 post-conception, with ciliogenesis regulated by the transcription factor Foxj1, which activates genes for motile cilia assembly.^[25]^[26] Timelines differ across species; human development is protracted, with alveolar maturation extending into childhood, whereas in mice, the saccular stage completes shortly postnatally (around birth to P5), with alveolarization beginning thereafter and largely completing by approximately postnatal day 28, reflecting differences in gestation length (mice ~19-21 days vs. human ~40 weeks) and branching generations (mice ~13 vs. human ~23).^[27]^[28]

Adult Stem Cells and Repair Mechanisms

The adult respiratory epithelium maintains its integrity through a hierarchical organization of stem and progenitor cells that enable tissue homeostasis and repair following injury. In the proximal airways, basal cells serve as multipotent progenitors, characterized by expression of transcription factor p63 and keratin 5 (KRT5), which allow them to self-renew and differentiate into secretory (e.g., goblet and club) and ciliated cells.^[29]^[30] In the bronchioles, club cells, marked by secretoglobin family 1A member 1 (SCGB1A1), act as facultative progenitors capable of replenishing the epithelial layer and, under certain conditions, contributing to alveolar repair.^[31]^[32] Distally, in the alveoli, type II alveolar epithelial cells (AT2) function as the primary stem cells, producing pro-surfactant protein C and differentiating into type I alveolar epithelial cells (AT1) to restore gas exchange surfaces.^[33] Upon injury, such as from viral infection or toxic exposure, these progenitors initiate repair through proliferation and differentiation. Basal cells in the airways rapidly expand and give rise to ciliated and goblet cells, a process regulated by Notch signaling that promotes secretory cell fate while suppressing excessive ciliogenesis.^[34] In severe damage, epithelial cells may undergo dedifferentiation, reverting to a progenitor-like state to facilitate regeneration, as observed in alveolar regions where mature cells reacquire stemness markers.^[35]^[36] Club cells in bronchioles similarly proliferate to replace lost epithelium, while AT2 cells in the distal lung undergo transitional states, including partial dedifferentiation, before maturing into AT1 cells.^[37] Key molecular markers highlight specialized subpopulations with enhanced stemness, particularly in distal regions. Lgr5-positive cells, often associated with Wnt signaling niches, contribute to progenitor maintenance in alveolar and bronchioalveolar junctions.^[38]^[39] Similarly, Scgb3a2-expressing subpopulations among club-like cells exhibit distal stemness, enabling plasticity toward alveolar lineages during repair.^[40]^[41] The transcriptional regulators YAP and TAZ play crucial roles in this process, driving AT2 proliferation and preventing fibrotic outcomes by integrating mechanical and signaling cues in the epithelial niche.^[42] Recent single-cell transcriptomic studies have revealed extensive cellular plasticity in the respiratory epithelium, underscoring dynamic repair mechanisms. For instance, 2025 analyses demonstrate AT2-to-AT1 transdifferentiation as a core pathway in alveolar regeneration, with intermediate states marked by co-expression of progenitor and mature markers.^[43] These atlases also highlight how aging impairs regenerative capacity, with AT2 cells showing senescence-associated declines in proliferation and differentiation potential, exacerbated by senescent-associated secretory phenotype (SASP) factors.^[44]^[45] Targeting pathways like p16INK4a has shown promise in reversing age-related AT2 dysfunction in preclinical models. A major challenge in repair is distinguishing adaptive regeneration from pathological fibrosis, where transforming growth factor-β (TGF-β) signaling inhibits epithelial proliferation and promotes mesenchymal transition.^[46]^[47] Elevated TGF-β in injured lungs shifts the balance toward fibroblast activation and extracellular matrix deposition, underscoring the need for therapies that modulate this pathway to favor epithelial recovery.^[48]^[49]

Physiology and Function

Barrier and Protective Roles

The respiratory epithelium serves as a primary physical barrier against inhaled environmental threats, including pathogens, allergens, and pollutants. Apical tight junctions, formed by transmembrane proteins such as occludin and claudins, seal the paracellular space between epithelial cells, preventing leakage and invasion by harmful agents. ^[50] These junctions maintain epithelial polarity and integrity, with occludin facilitating tight junction assembly and claudins regulating selective permeability. ^[50] Complementing this, a viscoelastic mucus layer overlays the epithelium, primarily composed of gel-forming mucins like MUC5AC and MUC5B secreted by goblet cells and submucosal glands. ^[51] This mucus traps particulate matter, such as dust and microbes, immobilizing them for subsequent removal and shielding underlying cells from direct exposure. ^[51] In addition to structural defenses, the epithelium deploys chemical barriers through secreted antimicrobial factors. Epithelial cells produce antimicrobial peptides, including β-defensins (e.g., HBD-1, HBD-2) and cathelicidins (e.g., LL-37), which exhibit broad-spectrum activity against bacteria, fungi, and viruses by disrupting microbial membranes. ^[52] These peptides are upregulated in response to infection, with concentrations reaching up to 1 μg/ml in airway fluids during inflammation. ^[52] Supporting this, enzymes like lysozyme (0.1–1 mg/ml in secretions) hydrolyze bacterial peptidoglycans, while lactoferrin (also 0.1–1 mg/ml) sequesters iron to starve pathogens and exerts direct bactericidal effects. ^[52] These components collectively inhibit microbial colonization on the epithelial surface. The epithelium also actively senses threats via innate immune receptors, bridging physical and adaptive defenses. Pattern recognition receptors, such as Toll-like receptors (TLRs 1–10, prominently TLRs 2–6) and NOD-like receptors (NLRs, including NOD1, NOD2, and NLRP3), detect pathogen-associated molecular patterns (PAMPs) like lipopolysaccharides or viral RNA on the cell surface or in the cytosol. ^[53] Activation triggers NF-κB signaling, leading to the release of proinflammatory cytokines, including IL-6 and IL-8 (CXCL8), which recruit neutrophils and other leukocytes to amplify the immune response. ^[53] This sensing mechanism ensures rapid orchestration of host defense without compromising barrier integrity. To optimize these protective functions, the epithelium regulates airway surface liquid (ASL) pH through bicarbonate secretion, maintaining a mildly acidic environment of approximately 6.5–7.0. ^[54] Bicarbonate (HCO₃⁻) is generated intracellularly via carbonic anhydrase and transported apically primarily through the cystic fibrosis transmembrane conductance regulator (CFTR) channel, with contributions from pendrin (SLC26A4). ^[54] This pH homeostasis enhances antimicrobial peptide efficacy, supports mucin unfolding for particle trapping, and prevents excessive acidification from pollutants or metabolic byproducts. ^[54] Additionally, ASL pH undergoes large oscillations during breathing, reaching up to 9.0 during inhalation to promote antimicrobial activity.^[55] Recent studies highlight potential therapeutic modulation of these barriers, particularly against pollutants. A 2024 investigation using human bronchial epithelial cells (16HBE14σ) demonstrated that flavonoids like luteolin and naringenin (at 30–50 μM) significantly enhance transepithelial electrical resistance, bolstering tight junction integrity and countering pollutant-induced disruption, while kaempferol showed milder effects without cytotoxicity. ^[56] These findings suggest flavonoids as adjuncts to reinforce epithelial resilience in polluted environments. ^[56]

Mucociliary Clearance and Secretion

The mucociliary escalator is a critical defense mechanism in the respiratory epithelium, where coordinated ciliary beating propels mucus-trapped particles toward the oropharynx for expulsion. Ciliated epithelial cells feature motile cilia that beat at a basal frequency of 10-20 Hz, generating metachronal waves that synchronize motion across the cell surface to efficiently move the mucus layer.^[57] This rhythmic activity is powered by dynein motor proteins, which drive microtubule sliding within the characteristic 9+2 axonemal structure of the cilia, enabling the forward propulsion of mucus at rates of 5-20 mm/min in the trachea, with speeds decreasing distally in smaller airways.^[57]^[58] The escalator's efficiency relies on the periciliary layer (PCL) beneath the mucus, where hydrated airway surface liquid (ASL) allows cilia to extend and beat freely without hindrance. Mucus secretion is primarily regulated by goblet and club cells in the surface epithelium, which release gel-forming mucins such as MUC5AC through Ca²⁺-dependent exocytosis of preformed granules. This process is triggered by intracellular Ca²⁺ elevations, often via purinergic receptor activation, leading to rapid fusion of mucin granules with the apical membrane.^[59] In proximal airways, submucosal glands provide a significant contribution to mucus production, secreting both mucins and fluid in response to stimuli, which helps initiate and sustain mucus flow onto the epithelial surface.^[60] These glands, embedded in the submucosa, release viscous strands of MUC5B that integrate with surface mucus to form a cohesive layer conducive to clearance. Neural and chemical signals finely tune both secretion and ciliary activity to maintain escalator function. Parasympathetic innervation via the vagus nerve stimulates acetylcholine (ACh) release, which binds muscarinic receptors on goblet cells and submucosal glands to enhance mucin secretion and glandular output.^[61] Concurrently, purinergic signaling through extracellular ATP and UTP activates P2Y₂ receptors on ciliated cells, increasing intracellular Ca²⁺ and thereby elevating ciliary beat frequency to accelerate mucus transport during threats like pathogen exposure.^[62]^[63] Optimal ASL hydration, maintained at a depth of approximately 7-10 μm, is essential for effective ciliary beating and mucus propulsion, with the PCL comprising about 7 μm to match outstretched cilia length. This volume is regulated by the balance of Cl⁻ secretion through CFTR channels and Na⁺ absorption via ENaC channels in epithelial cells; CFTR promotes hydration by driving Cl⁻ efflux and inhibiting ENaC, preventing ASL depletion that could collapse the periciliary space.^[64] Disruptions in this balance, such as reduced CFTR activity, lead to dehydrated ASL and impaired clearance. Recent advances highlight the integrated structure-function relationships in mucociliary clearance, including how ASL defects compromise pathogen expulsion. A 2024 study in Scientific Reports using a Xenopus tropicalis tadpole skin model demonstrated that loss of TMEM16A results in altered mucin maturation, with potential implications for ASL dehydration and defective mucociliary clearance, underscoring the role of chloride channels in maintaining mucus barrier integrity against infections.^[65]

Pathology and Clinical Significance

Epithelial Dysfunction in Diseases

In chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), dysfunction of the respiratory epithelium manifests through goblet cell metaplasia, which drives excessive mucus production and hypersecretion, primarily mediated by interleukin-13 (IL-13) signaling. In asthma, IL-13 stimulates goblet cell differentiation from progenitor cells, leading to mucus hypersecretion that obstructs airways and exacerbates inflammation. This metaplasia is a hallmark of type 2 inflammation, where IL-13 acts directly on epithelial cells to promote mucin gene expression, such as MUC5AC. In COPD, particularly in smokers, the epithelium experiences a loss of ciliated cells, impairing mucociliary clearance and allowing mucus accumulation, which contributes to chronic airflow obstruction. This reduction in ciliated cell density, often below 5% in severe cases compared to over 8% in healthy airways, stems from impaired differentiation and increased epithelial damage from chronic exposure to irritants. Infectious agents further disrupt respiratory epithelial integrity, with viruses like SARS-CoV-2 exploiting ACE2 receptors on the apical surface of airway epithelial cells to initiate infection, leading to widespread sloughing and subsequent fibrosis. SARS-CoV-2 preferentially infects ciliated and goblet cells via ACE2, causing cytopathic effects including cell shedding and denudation of the epithelial barrier, as observed in autopsy studies from 2020 onward. Research from 2020 to 2025 has highlighted how this infection triggers fibrotic remodeling through persistent inflammation and epithelial injury, with infected cells releasing pro-fibrotic cytokines that promote extracellular matrix deposition. In long COVID, persistent epithelial dysfunction persists beyond acute infection, characterized by immune-mediated barrier impairment, aberrant nasal and airway epithelial differentiation, and ongoing inflammation that contributes to chronic symptoms in up to 10% of cases.^[66] Bacterial pathogens, such as Pseudomonas aeruginosa, exacerbate epithelial disruption by invading tight junctions and inducing cytotoxicity, particularly in compromised airways. P. aeruginosa employs virulence factors like pyocyanin to breach the epithelial barrier, causing loss of tight junction integrity and facilitating chronic colonization, which perpetuates inflammation and mucus stasis. Genetic disorders underscore the epithelium's vulnerability, as seen in cystic fibrosis (CF), where mutations in the CFTR gene impair chloride transport, resulting in dehydrated airway surface liquid and viscous mucus that hinders clearance and predisposes to recurrent infections. CFTR dysfunction leads to hyperabsorption of sodium and water, concentrating mucus and promoting bacterial biofilms, which drive chronic neutrophilic inflammation in the epithelium. In primary ciliary dyskinesia (PCD), defects in dynein arms of ciliary axonemes abolish coordinated beating, causing ineffective mucociliary transport and recurrent respiratory infections from birth. These ultrastructural abnormalities, often involving outer or inner dynein arm absences, directly impair the motile function of ciliated epithelial cells, leading to mucus retention and bronchiectasis. Environmental injuries, including oxidant stress from cigarette smoke, induce squamous metaplasia in the respiratory epithelium, replacing normal pseudostratified cells with stratified squamous layers that lack mucociliary function and increase susceptibility to further damage. Smoke-generated reactive oxygen species disrupt epithelial differentiation, promoting metaplasia as a maladaptive repair response, with prevalence significantly higher in COPD patients compared to non-smokers. Air pollution, particularly particulate matter, triggers epithelial inflammation through oxidative stress and cytokine release, compromising barrier integrity and enhancing pathogen adhesion. Fine particles (PM2.5) induce IL-8 and IL-6 production in epithelial cells, fostering a pro-inflammatory milieu that amplifies remodeling and infection risk. Epithelial remodeling in these pathologies involves basement membrane thickening and epithelial-mesenchymal transition (EMT), contributing to fibrosis and airway wall stiffening. In asthma and COPD, persistent injury leads to collagen deposition beneath the epithelium, thickening the basement membrane 2- to 3-fold in severe cases, which anchors inflammatory cells and perpetuates dysfunction. EMT transforms epithelial cells into mesenchymal-like phenotypes, driven by TGF-β1, resulting in loss of E-cadherin and gain of vimentin, thereby generating myofibroblasts that deposit extracellular matrix and promote subepithelial fibrosis. This process is central to fibrotic progression, linking acute injury to chronic structural changes in the respiratory epithelium.

Emerging Therapies and Research

Recent advancements in regenerative therapies for the respiratory epithelium focus on stem cell-based approaches to repair damaged tissues. Basal cell-derived organoids have shown promise in reconstructing the epithelial layer when implanted into injured lung tissues, enabling functional regeneration of the airway epithelium in vivo.^[67] In 2025, breakthroughs in lung bioengineering utilized induced pluripotent stem cells (iPSCs) to generate vascularized organoids that mimic tracheal structures, integrating mesoderm and endoderm differentiation for enhanced tissue repair potential.^[68] These iPSC-derived models address challenges in tracheal reconstruction by promoting epithelial regeneration and integration with host tissues.^[69] Pharmacological interventions targeting the respiratory epithelium have advanced significantly, particularly with CFTR modulators for cystic fibrosis. The triple combination therapy elexacaftor/tezacaftor/ivacaftor, approved in 2019, corrects CFTR protein folding and function, leading to sustained improvements in lung function and sweat chloride levels in patients with at least one F508del mutation.^[70] Long-term data through 2025 confirm its safety and efficacy in children and adults, with continued enhancements in pulmonary function and reduced exacerbations.^[71] For asthma, anti-IL-13 therapies mitigate goblet cell metaplasia by inhibiting mucus hypersecretion and airway remodeling, as IL-13 drives epithelial changes that exacerbate inflammation.^[72] In vitro models for drug delivery to the respiratory epithelium have evolved to better assess permeability and efficacy. Air-liquid interface (ALI) cultures of primary airway epithelial cells replicate the mucociliary barrier, enabling precise evaluation of drug transport and epithelial interactions from 2021 onward.^[73] Organ-on-chip systems, reviewed between 2021 and 2025, incorporate dynamic airflow and mechanical cues to simulate breathing, facilitating high-throughput testing of inhaled therapeutics on epithelial permeability.^[74] These models have accelerated the development of targeted delivery strategies by mimicking in vivo conditions more accurately than traditional monolayers.^[75] Future directions in research emphasize gene editing and natural compounds to restore epithelial function. CRISPR-Cas9 has been applied to correct ciliary defects in primary ciliary dyskinesia models, enabling precise restoration of motile cilia in airway organoids derived from patient iPSCs.^[76] A 2024 study demonstrated that flavonoids such as kaempferol, luteolin, and naringenin enhance barrier integrity in human bronchial epithelial cells by upregulating tight junction proteins and reducing permeability.^[77] Ongoing clinical trials highlight innovative approaches to improve mucociliary clearance and targeted delivery. Phase III trials of mucolytics like hypertonic saline and carbocisteine in bronchiectasis, completed in 2025, evaluated their role in reducing exacerbations through enhanced sputum clearance, though results indicated limited overall efficacy in stable patients.^[78] Nanotechnology-based systems, including mucus-penetrating nanoparticles functionalized for epithelial targeting, have advanced to preclinical and early clinical stages, enabling prolonged drug retention in the airways for conditions like asthma.^[79] These carriers overcome mucus barriers to deliver anti-inflammatory agents directly to the epithelium, showing reduced inflammation in murine models.^[80]

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Modulation of the Respiratory Epithelium Physiology by Flavonoids ...
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Lung mucus production and mucociliary clearance
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Prolonged increase in ciliary beat frequency after short‐term ...
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Air-liquid interface (ALI) impact on different respiratory cell cultures
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Modulation of the Respiratory Epithelium Physiology by Flavonoids ...
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Airway epithelial-targeted nanoparticle reverses asthma in ...
This study demonstrates that FcBP-functionalized PEG-NP can overcome multiple obstacles in the airway to prolong the pulmonary retention of drugs.
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Nanotechnology-Based Therapeutics for Airway Inflammatory ...
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