Han S, Zhou AX, Jamieson AM
… +26 more, Wilson AA, Zhou B, Weiss DJ, Jiang D, McKeon F, Chapman H, Miranda H, Schiller HB, Rajagopal J, Yun JH, Que J, Engelhardt JF, Basil MC, Raredon MSB, Gu M, Ghosh M, Kadur Lakshminarasimha Murthy P, Tata PR, Wang R, Davidson S, Majka SM, Tesfaigzi Y, Gomez CR, Lu Q, Ordovas-Montanes J, Kalhan R
Am J Respir Cell Mol Biol
· 2026 May · PMID 42202213
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Lung function peaks in young adulthood and declines with age. Studies suggest that this trajectory may be modifiable, potentially enhancing lung health and resilience to prevent or delay the onset of chronic lung disease...Lung function peaks in young adulthood and declines with age. Studies suggest that this trajectory may be modifiable, potentially enhancing lung health and resilience to prevent or delay the onset of chronic lung disease. Although significant progress has been made in identifying the lung stem/progenitor cell populations involved in lung repair and homeostasis, their regulation and potential for manipulation to promote respiratory health and resilience remain elusive. To explore these issues, the NHLBI organized a virtual workshop on November 7-8, 2024 that aimed to cover the current scientific landscape, address critical research gaps, and identify challenges, opportunities, and key research questions related to chronic lung disease, with a focus on lung stem/progenitor resilience and its applications in the early diagnosis, prevention, and treatment of chronic lung diseases. This report summarizes the scientific presentations, discussions, and recommendations from the workshop.
Elmadbouh I, Zhong Z, Wang L
… +9 more, Chikoore S, Endoni B, Sah A, Thompson M, Hoeppner LH, Prakash YS, Yuan JX, Pabelick CM, Babicheva A
Am J Respir Cell Mol Biol
· 2026 May · PMID 42184280
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Endothelial-to-mesenchymal transition (EndMT) is a biological process through which lung vascular endothelial cells (ECs) transdifferentiate into mesenchymal-like cells. EndMT has recently been implicated in the developm...Endothelial-to-mesenchymal transition (EndMT) is a biological process through which lung vascular endothelial cells (ECs) transdifferentiate into mesenchymal-like cells. EndMT has recently been implicated in the development and progression of pulmonary vascular remodeling in pulmonary hypertension (PH); however, its underlying regulatory mechanisms remain incompletely understood. MicroRNAs (miRNAs) are key post-transcriptional regulators of EC gene expression and cellular responses to various stimuli. Notably, microRNA-153 (miR-153) has been shown to directly target SNAI1 to modulate epithelial-to-mesenchymal transition (EMT), a process closely related to EndMT and extensively studied in cancer. Whether miR-153 also participates in EndMT regulation, however, remains unknown. In this study, we demonstrate that 72-hour hypoxic exposure induces SNAI1-mediated EndMT in human lung vascular ECs. Hypoxia also increased cell proliferation and disrupted intercellular junctions, leading to enhanced endothelial permeability. Reduced miR-153 expression was observed in both hypoxia- and TGF-β1-induced EndMT, as well as in ECs isolated from PH patients exhibiting an EndMT phenotype. Similar to hypoxia, TGF-β1 promoted EC permeability. Loss of miR-153 enhanced SNAI1-mediated EndMT, endothelial survival, and permeability under normoxic conditions, whereas miR-153 overexpression attenuated EndMT induced by hypoxia or TGF-β1. However, miR-153 restoration did not completely restore endothelial barrier integrity disrupted by these stimuli. In vitro findings were validated in experimental PH model. In conclusion, miR-153 serves as a critical regulator of EndMT, maintaining endothelial identity and barrier function. Therapeutic delivery of miR-153 may therefore represent a novel strategy to inhibit EndMT and attenuate pulmonary vascular remodeling in PH.
Berthiaume Fox KA, Iannuzo N, Li J
… +10 more, Rojas-Quintero J, Kimura H, Santiago Raj PV, Schnellmann RG, Johnson MDL, Polverino F, Langlais PR, Kraft M, Park JA, Ledford JG
Am J Respir Cell Mol Biol
· 2026 May · PMID 42154955
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Recent evidence suggests that bronchial epithelial cells from individuals with asthma exhibit altered metabolic signatures. This metabolic shift of energetically demanding cells leads to increased inflammation, excessive...Recent evidence suggests that bronchial epithelial cells from individuals with asthma exhibit altered metabolic signatures. This metabolic shift of energetically demanding cells leads to increased inflammation, excessive reactive oxygen species production (ROS), and oxidative stress-all hallmarks of mitochondrial dysfunction. While mitochondrial dysfunction has been implicated in disruption in epithelial cell function in asthma, the mechanistic link between bronchoconstriction observed in asthma and these metabolic alterations remains poorly defined. Club cell secretory protein (CC16) is the most abundant protein found in the lung and exerts key anti-inflammatory and antioxidant functions contributing to protection against airway remodeling. Decreased levels of CC16 in both serum and bronchial alveolar lavage fluid (BALF) are characteristic of asthma and worsening respiratory disease. Using a well-established transmembrane compression system to model bronchoconstriction coupled with mass spectrometry and quantitative proteomics, we investigated how modeling bronchoconstriction in airway cells impacts CC16 expression and cell metabolic pathway changes over time. Using naive mouse tracheal epithelial cells (MTECs) and normal human bronchial epithelial cells (HBECs), we observed that recombinant (r)CC16 induces the expression of proteins related to various metabolic pathways, such as glycolysis, gluconeogenesis, and the pentose phosphate pathway and that compression of airway cells results in acute decreases in CC16 expression, as well as decreases in metabolic processes. MTECs deficient in CC16 (CC16-/-) had lower mitochondrial oxygen consumption rate (OCR) compared to WT cells. Exogenous addition of rCC16 significantly increased OCR of both WT and CC16 deficient MTECs. Our findings suggest a novel role for CC16 in mediating airway epithelial cell metabolic processes, which could be decreased by bronchoconstrictive events in human asthma. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD067703.
Wu M, Wang H, Huang Y
… +6 more, Wang L, Xu Y, Li C, Yang M, Chen B, Pan J
Am J Respir Cell Mol Biol
· 2026 May · PMID 42153339
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Severe coagulation and endothelial dysfunction are characteristics of sepsis-induced acute pulmonary coagulopathy with high morbidity and mortality. The primary objective of this research is to investigate the role rFGF1...Severe coagulation and endothelial dysfunction are characteristics of sepsis-induced acute pulmonary coagulopathy with high morbidity and mortality. The primary objective of this research is to investigate the role rFGF10 in ameliorating sepsis-induced coagulation and endothelial dysfunction. FGF10 expression levels in sepsis-induced mice lung tissues and lipopolysaccharide (LPS) stimulated Human umbilical vein endothelial cells (HUVECs) were detected and the results showed that they were both elevated. Supplementation with rFGF10 protected HUVECs against LPS stimulation and ameliorated sepsis-induced pulmonary coagulation evidenced by the suppressed coagulation factors and alleviated lung injury. Mechanistically, rFGF10 activated Nrf2-modulated mitophagy by PINK1/Parkin pathway in septic mice, which maintained mitochondrial quality, promoted activities of anti-oxidation and suppressed mitochondrial reactive oxygen species (mtROS), therefore, suppressed phosphorylation of NF-𝑘B, Erk1/2 and P38, which thus, is crucial for rFGF10 protection against sepsis induced pulmonary coagulation. Suppression of Nrf2 with its inhibitor ML385 abolished all beneficial effects of rFGF10 on sepsis-induced mice. These findings revealed the therapeutic effects of rFGF10 on sepsis-induced pulmonary coagulation and endothelial dysfunction, which could be a potential pharmacological strategy for clinic.
Wu X, Li Y, Lin X
… +5 more, Yu Z, Mu S, Li X, Liu J, Han Y
Am J Respir Cell Mol Biol
· 2026 May · PMID 42153337
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Recent investigations show that mitochondrial impairment significantly contributes to endothelial damage in septic acute respiratory distress syndrome (ARDS). Humanin (HN) and its derivative Humanin-G (HNG) are mitochond...Recent investigations show that mitochondrial impairment significantly contributes to endothelial damage in septic acute respiratory distress syndrome (ARDS). Humanin (HN) and its derivative Humanin-G (HNG) are mitochondrial polypeptides which have been identified as inhibitors of cellular apoptosis and neuroprotective agents against oxidative stress. This study aims to elucidate the effects of HNG on pulmonary vascular endothelial damage. In septic ARDS patients, serum concentrations of HN increased markedly on Day 1, followed by a progressive decrease from Day 3 to Day 7. A murine model of septic ARDS was established through intraperitoneal injection of lipopolysaccharide. The results showed that HNG pretreatment significantly reduced inflammatory factor expression in both in vivo and in vitro settings, as confirmed by qPCR and Western blot. Furthermore, HNG treatment conferred protection against lung injury, restored mitochondrial morphology, improved mitochondrial respiratory function, and corrected impaired membrane potential, as assessed by H&E staining, transmission electron microscopy, Seahorse analysis, and JC-1 staining, respectively. Additionally, protein-peptide interaction analysis suggested that HNG binds to the interleukin-6 receptor alpha, and immunoprecipitation confirmed that HNG competitively interacts with the IL-6 receptor family in comparison to IL-6. Furthermore, WB analysis indicated that the protective effects of HNG on mitochondria may be largely due to the suppression of STAT3 expression in septic lung endothelial cells. In summary, this study suggests that the administration of the mitochondrial peptide HNG confers protective effects and mitigates mitochondrial damage by inhibiting the downstream pro-inflammatory pathways of IL-6/STAT3 in the pulmonary vascular endothelial cells of septic ARDS.
Ding H, Liu J, Gong Y
… +5 more, Wang K, Yu R, Liu Y, Lai X, Cao J
Am J Respir Cell Mol Biol
· 2026 May · PMID 42153329
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RATIONALE: Bacterial pneumonia is a common acute respiratory infection. The role of Meteorin-like (METRNL) in bacterial pneumonia is unknown. OBJECTIVES: To investigate the clinical and functional role of METRNL in bacte...RATIONALE: Bacterial pneumonia is a common acute respiratory infection. The role of Meteorin-like (METRNL) in bacterial pneumonia is unknown. OBJECTIVES: To investigate the clinical and functional role of METRNL in bacterial pneumonia. METHODS: METRNL levels were examined in the animals and patients with bacterial pneumonia. Multiple genetic and pharmacologic approaches were used to investigate METRNL-mediated host immune responses during bacterial pneumonia. MEASUREMENTS AND MAIN RESULTS: METRNL production was dramatically suppressed in response to acute bacterial lung infection. METRNL loss increased mortality and bacterial burden during Pseudomonas aeruginosa and Staphylococcus aureus pneumonia, but had no effects on Aspergillus fumigatus and influenza virus pnuemonia. Conversely, METRNL overexpression resulted in decreased mortality and bacterial burden from bacterial pneumonia. Furthermore, therapeutic administration of recombinant METRNL protein improved mortality and bacterial clearance in a neutrophil-dependent manner after bacterial pneumonia. METRNL enhanced bacterial phagocytosis and subsequent killing capacity of neutrophils, and conditional knockout of KIT receptor tyrosine kinase in neutrophils abolished METRNL-mediated protection against bacterial pneumonia. Furthermore, the increased antibacterial functions of neutrophils elicited by the METRNL-KIT axis was mediated through adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. The augmented antibacterial effects of METRNL on neutrophils were also confirmed in humans, and circulating METRNL levels were reduced in patients with bacterial pneumonia, which might serve as a new biomarker for patient stratification and therapeutic guidance. CONCLUSIONS: This study suggests that a potential theranostic approach involving METRNL-guided patient stratification and targeted therapy using METRNL rescue therapy may help improve the management of patients with bacterial pneumonia.
Evans EM, Mayday MY, Pearce EM
… +32 more, Iwanaga K, Ly NP, Church GD, Reyes G, Simon MR, Blum J, Kim H, Mu J, Baez-Maidana J, Auletta JJ, Shaw PJ, Kreml EM, Martin PL, Duncan CN, Rowan CM, Godder K, Hurley C, Cuvelier GDE, Qayed M, Abdel-Azim H, Keating AK, Fitzgerald JC, Hanna R, Killinger JS, Hume JR, Quigg TC, Castillo P, Satwani P, Moore TB, Dvorak CC, Zinter MS, Pediatric Transplantation And Cell Therapy Consortium
Am J Respir Cell Mol Biol
· 2026 May · PMID 42150759
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RATIONALE: Lung injury after hematopoietic stem cell transplantation (HCT) occurs due to infection, chemotherapy toxicity, and alloreactive inflammation. Analyses of bronchoalveolar lavage (BAL) fluid have revealed domin...RATIONALE: Lung injury after hematopoietic stem cell transplantation (HCT) occurs due to infection, chemotherapy toxicity, and alloreactive inflammation. Analyses of bronchoalveolar lavage (BAL) fluid have revealed dominant pathobiologic signatures, but minimally-invasive diagnostics are needed. OBJECTIVES: To determine whether microbiome and gene expression perturbations are shared along the respiratory tract or isolated to the alveoli in pediatric HCT patients with lung injury. METHODS: We performed bulk RNA sequencing on 206 paired nasal and BAL samples from 160 HCT patients and 17 healthy controls enrolled at 28 children's hospitals (2016-2025). Microbial and human transcripts were compared using multivariable models accounting for age, sex, and paired sampling. MEASUREMENTS AND MAIN RESULTS: HCT BAL and nasal transcriptomes differed across 13,698 genes, 48 cellular components, and network interactions linking inflammation, reactive oxygen species, and immunometabolism. Minimal BAL-nasal correlation was observed in gene expression levels (median ρ = 0.03, IQR -0.03 to 0.08) or fractional abundance of key cells such as neutrophils and CD8 + T-cells. BAL microbiomes harbored fewer commensal bacteria and more fungi and DNA viruses. BAL bacterial RNA was associated with diminished immune signaling whereas nasal bacterial RNA aligned with inflammatory gene expression. Further, only BAL microbial RNA was linked to transcriptional shifts in epithelial injury response, keratinization, and collagen deposition. Finally, BAL commensal microbiome depletion, epithelial injury, and immune dysregulation signatures were associated with death or prolonged mechanical ventilation, whereas nasal samples provided minimal prognostic information. CONCLUSIONS: These data support alveolar compartmentalization in pediatric HCT and emphasize the ongoing need for minimally-invasive but informative diagnostics.
Horner RL, Wellman DA, Sands SA
… +2 more, Azarbarzin A, Taranto-Montemurro L
Am J Respir Cell Mol Biol
· 2026 Jul · PMID 42148507
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Obstructive sleep apnea (OSA) is the most prevalent sleep-related breathing disorder and is associated with cardiovascular, metabolic, neurocognitive, and mortality risk. OSA arises from recurrent upper airway collapse d...Obstructive sleep apnea (OSA) is the most prevalent sleep-related breathing disorder and is associated with cardiovascular, metabolic, neurocognitive, and mortality risk. OSA arises from recurrent upper airway collapse during sleep, producing intermittent hypoxia and sleep fragmentation. While anatomical vulnerability contributes to airway instability, a key determinant of OSA pathophysiology is the sleep-related reduction in upper airway neuromuscular activity that occurs at the wake-sleep transition. Despite this central role, no approved pharmacologic therapies have targeted the neuromuscular mechanisms underlying airway collapse. This review summarizes the biological basis of upper airway neuromuscular dysfunction in OSA, integrating insights from preclinical models of hypoglossal motor control with clinical evidence supporting neuromodulatory treatment strategies. We focus on AD109, an investigational oral therapy combining a norepinephrine reuptake inhibitor (atomoxetine) with an antimuscarinic agent (aroxybutynin), designed to counteract sleep-related withdrawal of excitatory noradrenergic drive and rapid eye movement (REM)-related muscarinic inhibition at the hypoglossal motor nucleus. Early phase clinical studies demonstrated rapid and substantial improvements in airway collapsibility and apnea-hypopnea index, providing proof of concept for this approach. Results from large phase 3 trials confirm that targeting neuromuscular dysfunction can produce reductions in airway obstruction and meaningful improvements in oxygenation, including hypoxic burden, a metric closely linked to OSA-related sequelae. Symptomatic patients also experienced improvements in fatigue, sleepiness, and snoring versus placebo. Together, these findings support neuromuscular dysfunction as a tractable therapeutic target in OSA and highlight the potential of pharmacologic strategies to address both the physiological consequences of intermittent hypoxia and patient-relevant outcomes across a broad and heterogeneous OSA population.
Saavedra MT, Rysavy NM, Poch KE
… +13 more, Caceres SM, Leach SM, Laborda C, Leti F, Walton KN, Danhorn T, Reisz JA, D'Alessandro A, Taylor-Cousar JL, Nick JA, Reinhardt RL, Bratcher PE, Vestal BE
Am J Respir Cell Mol Biol
· 2026 May · PMID 42118592
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RATIONALE: Elexacaftor-tezacaftor-ivacaftor (ETI) broadly improves outcomes in cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) correction by ETI is incomplete, and patients with establish...RATIONALE: Elexacaftor-tezacaftor-ivacaftor (ETI) broadly improves outcomes in cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) correction by ETI is incomplete, and patients with established disease continue to experience infection. We hypothesized that CFTR restoration by ETI would modify T cell memory, providing a basis for improved infectious outcomes after treatment. OBJECTIVES: To evaluate ETI modification of lymphocyte signatures using transcriptomics and metabolomics, in blood samples taken from adults with CF (awCF). METHODS AND MAIN RESULTS: Circulating CD3 + T cells from awCF (n = 18) before and after ETI initiation were evaluated by CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by sequencing). Single cell data profiled multiple T cell populations, including naive, memory, and effector states, with the most extensive changes occurring in CD4 + T populations. Simultaneous plasma metabolomic measurements were analyzed in association with CD4 + T cell metabolic gene signatures. The relationships between clinical outcomes, cell-specific gene expression and metabolomics were evaluated using generalized linear mixed models. The effect of reduced CFTR in lymphocytes was evaluated in vitro utilizing CRISPR/Cas9-mediated CFTR knockdown in primary human lymphocyte cultures, as well in splenocytes harvested from CFTR knockout mice. CONCLUSIONS: We reveal that altered metabolism occurs within the CD4 + T memory compartment following CFTR modulation, identifying multiple previously unrecognized changes in memory functions. Memory T cell metabolic switches are highly related to reduction in hospitalizations after treatment. Adaptive immune memory in awCF after modulator therapy is highly associated with improved outcomes from CF pulmonary infections, with variation seen in individuals experiencing lesser benefit after modulators.
Nguyen J, Van C, Olverson ZA
… +11 more, Sampath N, Posham L, Karpurapu M, Kim J, Lee TJ, Yoo JY, Gorr MW, Pabla N, Wold LE, Christman JW, Chung S
Am J Respir Cell Mol Biol
· 2026 May · PMID 42113903
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RATIONALE: Macrophages are key drivers of allergic airway inflammation, but the mitochondrial mechanisms regulating these responses remain incompletely defined. Mitochondrial transcription factor A (TFAM) is essential fo...RATIONALE: Macrophages are key drivers of allergic airway inflammation, but the mitochondrial mechanisms regulating these responses remain incompletely defined. Mitochondrial transcription factor A (TFAM) is essential for mitochondrial DNA (mtDNA) maintenance and mitochondrial homeostasis. OBJECTIVES: To define the role of myeloid TFAM in mitochondrial stress, senescence, allergic airway inflammation, and response to senolytic therapy. METHODS: Allergic airway inflammation was induced with dust mite, ragweed, and Aspergillus (DRA) in myeloid-specific TFAM-deficient mice TFAMfl/flLysMcre and littermate controls. Inflammatory, remodeling, mitochondrial, and senescence-associated outcomes were assessed in vivo and in macrophage-based mechanistic studies, including human alveolar macrophages. ABT-263 was used to evaluate senolytic responsiveness. MEASUREMENTS AND MAIN RESULTS: Myeloid TFAM deficiency worsened DRA-induced airway inflammation, eosinophilia, goblet cell hyperplasia, and collagen deposition, and increased pulmonary inflammatory, cGAS-STING, and senescence-associated markers. TFAM-deficient macrophages showed reduced mitochondrial mass and mitochondrial gene expression, increased cytosolic mtDNA, and greater susceptibility to TGF-β-induced senescence. In human alveolar macrophages, IL-4 decreased TFAM expression and mtDNA content, increased cytosolic mtDNA, and induced senescence-associated genes. ABT-263 suppressed IL-4-induced senescence and inflammatory gene expression in macrophages and reduced eosinophilia and inflammatory mediator production in allergen-challenged control mice, but these effects were largely lost in TFAMfl/flLysMcre mice. CONCLUSIONS: Myeloid TFAM limits mtDNA stress, senescence-associated inflammation, and allergic airway pathology, and influences responsiveness to senolytic therapy.
The pulmonary vasculature develops in close association with the airways and this network expands through the interactions between endothelial cells and the surrounding mesenchymal cells, the pericytes. Emerging evidence...The pulmonary vasculature develops in close association with the airways and this network expands through the interactions between endothelial cells and the surrounding mesenchymal cells, the pericytes. Emerging evidence suggests that pericytes play a significant role in various lung diseases, such as congenital diaphragmatic hernia and chronic obstructive pulmonary disease. However, characterizing pericytes remains challenging, impeding our understanding of their exact role in lung development and disease. Therefore, we used a novel cell tracing technology based on a bacterial DNA cytosine methyltransferase (Dcm) fused to RNA polymerase II (DCM-TM) to methylate active genes. The doxycycline inducible Dcm-PolII fusion protein was activated at specific time points during gestation, while the epigenetically labeled genes were analyzed at later time points. This retrospective cell tracing was coupled to single-cell RNA sequencing to track the development of mouse pulmonary pericytes at the single cell level. This revealed the paths to differentiation of perivascular progenitors into pericytes and vascular smooth muscle cells. Temporal analysis uncovered dynamic gene expression profiles during pericyte differentiation, highlighting pathways crucial for pulmonary vascular development. Further analysis showed intricate signaling interactions between pericyte progenitors and mature pericytes, and we validated MCAM as a bona fide pulmonary pericyte marker. Our findings challenge conventional views on pericyte origin and underscore the importance of accurate pericyte identification in developmental and disease contexts. Overall, this study enhances our understanding of pulmonary pericyte ontogeny and differentiation, offering insights into their potential as therapeutic targets in pericyte-associated lung diseases.
RATIONALE: Chronic cough patients present with increased airway sensory nerve density-a pathology often initiated by recurrent viral infections, notably H1N1. Infection-induced IFN-γ acts via its highly expressed recepto...RATIONALE: Chronic cough patients present with increased airway sensory nerve density-a pathology often initiated by recurrent viral infections, notably H1N1. Infection-induced IFN-γ acts via its highly expressed receptors to promote neurite outgrowth in vitro. OBJECTIVES: To investigate the role of IFN-γ as a mediator in the development of airway hyperinnervation and cough hypersensitivity induced by recurrent H1N1 viral infections. METHODS: We studied the effects and underlying mechanisms of recurrent H1N1 viral infections on airway hyperinnervation and subsequent cough hypersensitivity. MEASUREMENTS AND MAIN RESULTS: Recurrent H1N1 viral infections in mice significantly enhanced cough sensitivity and airway inflammation, accompanied by elevated pulmonary IFN-γ + T cells/IFN-γ levels, vagal CDK5 activity, and airway nerve density. Anti-IFN-γ treatment abrogated these effects-cough hypersensitivity, IFN-γ + T cell infiltration, CDK5 upregulation, and airway hyperinnervation. Roscovitine treatment markedly attenuated viral infection-induced cough hypersensitivity, CDK5 activation in vagal ganglia, and airway hyperinnervation. Viral infections did not change gene expressions of IFN-γ receptors in vagal ganglia. Neither anti-IFN-γ nor roscovitine alleviated viral infection-induced airway inflammation. No evidence of airway hyperinnervation was observed following a single-dose H1N1 infection, either in the short term or long term. IFN-γ sensitized mouse vagal sensory neurons. Pharmacological inhibition of the JAK-ERK1/2-CDK5 pathways decreased IFN-γ-induced neurite outgrowth in mouse vagal sensory neurons. CONCLUSIONS: Recurrent H1N1 viral infections may cause airway hyperinnervation and cough hypersensitivity via the IFN-γ-JAK-ERK1/2-CDK5 pathways. Recurrent H1N1 viral infection-induced cough hypersensitivity may be mediated, in part, by IFN-γ-mediated airway hyperinnervation.