Scribe C, Gonçalves D, Gautier-Isola M
… +16 more, Dellugat P, Rignol G, Ghilain C, Marsault R, Etasse L, Truchi M, Cadis H, Mille J, Guardini L, Vassaux G, Delgado Cohen J, Pizarro JG, Cheng SH, Czech C, Mari B, Herbert C
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 41738290
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Fibroblast growth factor (FGF) signaling plays an important role in the pathogenesis of various respiratory diseases, including idiopathic pulmonary fibrosis (IPF). FGF ligands can exert both pro- and anti-fibrotic effec...Fibroblast growth factor (FGF) signaling plays an important role in the pathogenesis of various respiratory diseases, including idiopathic pulmonary fibrosis (IPF). FGF ligands can exert both pro- and anti-fibrotic effects, depending on the responding cell, the expression levels of FGF receptors (FGFR1-4) and the context of other signaling molecules such as Transforming growth factor β (TGF-β). We evaluated here the effect of a modified version of a soluble FGFR3 decoy receptor (designated as "sFGFR3-Fc"), that specifically sequesters pro-fibrotic FGFR3 ligands, FGF1, FGF2 and FGF9 as a potential anti-fibrotic drug. We showed that FGF2 stimulated proliferation and expression of various fibrotic markers in human pulmonary fibroblasts from healthy donors and IPF patients. The sFGFR3-Fc was able to reduce these FGF2-mediated responses and also partially attenuate the pro-fibrotic phenotype induced by TGF-β, including gel contraction. Furthermore, single cell transcriptomic analyses revealed heterogeneity of IPF-derived fibroblasts for FGF2 response and confirmed the potential efficacy of sFGFR3-Fc in decreasing the expression of a subset of TGF-β1 pathway genes. Finally, sFGFR3-Fc was shown to improve the progression of pulmonary fibrosis using both a preventive and therapeutic strategy, evaluated in the standard single bleomycin (BLM) instillation mouse model as well as in a more severe model of repeated BLM instillations, as evidenced by the reduction in ECM deposits, the recovery of body weight and the restoration of lung function. Our data highlight the interplay between the TGF-β and the FGF signaling pathways and demonstrate the potential of targeting pro-fibrotic FGFR3 ligands as therapeutic strategy for IPF.
Am J Respir Cell Mol Biol
· 2026 Jul · PMID 41738289
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RATIONALE: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants. We previously established the NLRP3 inflammasome as critical in the pathogenesis of BPD. The hyaluronan receptor CD44 interacts wi...RATIONALE: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants. We previously established the NLRP3 inflammasome as critical in the pathogenesis of BPD. The hyaluronan receptor CD44 interacts with TLR4 to propagate extracellular signals driving inflammation. The role of CD44 in BPD is unclear. OBJECTIVES: To determine the contribution of CD44 to NLRP3 inflammasome activation and the development of BPD. METHODS: The activation of the NLRP3 inflammasome and the development of BPD were studied in CD44 and TLR4 knockout (KO) mice. Lipopolysaccharide (LPS) was used to study TLR4-specific responses. MEASUREMENTS AND MAIN RESULTS: In normal mice, lung CD44 decreased in the first 2 postnatal weeks but increased with exposure to neonatal hyperoxia. CD44 KO mice exposed to hyperoxia were protected from decreased alveolarization and inflammatory responses. Increased IL-1β mRNA and protein and cleaved caspase-1 observed in CD44 wild-type (WT) mice were not seen in CD44 KO mice, indicating a failure to activate the NLRP3 inflammasome. Intraperitoneal LPS resulted in increased plasma IL-1β concentrations in CD44 WT mice, which were decreased in CD44 KO mice. Intratracheal LPS caused a neutrophilic inflammation in CD44 WT lungs, which was absent in CD44 KO mice. TLR4 KO mice were protected from neonatal hyperoxia and showed less lung IL-1β and inflammation. Increased lung CD44 expression was observed in the lungs of preterm baboons developing experimental BPD and in the lungs of preterm-born humans at extended corrected ages. CONCLUSIONS: Collectively, these data implicate CD44 in the pathogenesis of BPD and identify a novel therapeutic target to limit NLRP3 inflammasome activation.
Bernard O, Kwon M, Looney MR
… +2 more, Magnen M, Yu MA
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 41738286
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Pseudomonas aeruginosa (PA) is responsible for significant morbidity and mortality particularly in patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis...Pseudomonas aeruginosa (PA) is responsible for significant morbidity and mortality particularly in patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis (CF) as well as hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). The rise of antibiotic-resistant PA strains necessitates alternative treatment strategies. Among the different toxins secreted by PA, Exotoxin-A (Exo-A) becomes cytotoxic when cleaved by furin. This study investigates the therapeutic potential of furin inhibitor BOS-318 in mitigating acute lung injury induced by Exo-A and PA infection. Furin inhibition significantly improved survival rates and reduced lung injury in mouse pneumonia models using Exo-A and PA103. Additionally, BOS-318 accelerated bacterial clearance in vivo, and increased phagocytosis by alveolar macrophages. Bulk RNA-seq done on whole lung homogenate at 6 h revealed an immune profile with decreased natural killer (NK) cell signaling in the BOS-318-treated group, possibly due to a decrease in NK recruitment observed at 24 h, suggesting a role of furin in shaping the immune response. Moreover, administration of BOS-318 as a therapeutic strategy results in a protection of the lung epithelium. Overall, our findings demonstrate that furin inhibition protects against PA-induced acute lung injury and hastens bacterial clearance. These results are the first to characterize furin inhibition in animal models and supports its potential use as an adjunctive therapeutic strategy for treating PA infections.
Nho RS, Nielsen L, Roberts J
… +11 more, Diep S, Taylor A, Hager K, Yengo R, Rosas L, Farkas L, Prasad J, Mebratu YA, Rojas M, Chan SY, Horowitz JC
Am J Respir Cell Mol Biol
· 2026 Jul · PMID 41738284
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Lactate is increased in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and in mice with experimental lung fibrosis, and lactate has been linked to the pathogenesis of lung fibrosis. IPF fibroblasts in hyp...Lactate is increased in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and in mice with experimental lung fibrosis, and lactate has been linked to the pathogenesis of lung fibrosis. IPF fibroblasts in hypoxic conditions generate increased lactate due to an imbalance of lactate dehydrogenase isoforms that induce pyruvate conversion to lactate. Monocarboxylate transporter 4 (MCT4) functions as a key lactate export protein, but its role has not been studied in lung fibrosis. We hypothesized that MCT4 would have a critical role in the ability of IPF fibroblasts to generate extracellular lactate and found that MCT4 was significantly upregulated in IPF fibroblasts under hypoxic conditions. In contrast, the lactate importer protein, monocarboxylate transporter 1 (MCT1) did not significantly change in control or IPF fibroblasts. Pharmacologic inhibition and silencing of MCT4 reduced extracellular lactate generation by IPF fibroblasts. Supporting its role in lung fibrogenesis, MCT4 was increased in bleomycin-injured mice and in lungs from IPF patients. Importantly, normal fibroblasts incubated with conditioned media from IPF fibroblasts exposed to hypoxic conditions had increased α-smooth muscle actin expression that was attenuated by inhibition of MCT4 in the donor IPF fibroblasts or by inhibition of the lactate receptor GPR-81 in the recipient normal fibroblasts. Together, these findings implicate MCT4 in the ability of IPF fibroblasts to increase extracellular lactate and highlight the role of lactate signaling via G-protein coupled receptor-81 in normal fibroblast differentiation. We propose a novel paradigm in which lactate export, driven by increased MCT4 expression, promotes fibrosis in oxygen-deficient microenvironments.
Giannini HM, Kan M, Cosgriff CV
… +15 more, Morley MP, Miano TA, Narayanan N, Ittner CAG, Turner AP, Esperanza MP, Erlich MC, Oniyide O, Anderson BJ, Jones TK, Feng R, Reilly JP, Himes BE, Shashaty MGS, Meyer NJ
Am J Respir Cell Mol Biol
· 2026 Jul · PMID 41738283
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Transcriptomic analysis of blood cells can reveal key elements of the dysregulated host response in sepsis and spur biomarker and mechanism identification. We hypothesized that sepsis nonsurvivors exhibit a distinct tran...Transcriptomic analysis of blood cells can reveal key elements of the dysregulated host response in sepsis and spur biomarker and mechanism identification. We hypothesized that sepsis nonsurvivors exhibit a distinct transcriptional signature in whole blood that reflects insights into sepsis mortality. We conducted a prospective observational cohort study of 161 critically ill sepsis patients. Whole blood RNA was collected within 24 hours of intensive care unit admission. Gene expression levels were measured using microarrays, and changes in gene levels were compared between 30-day nonsurvivors and survivors, adjusting for age, sex, and neutrophil count. Pathway overrepresentation analysis and weighted gene co-expression analysis were performed to identify biological pathways and gene co-expression groups, respectively, associated with sepsis mortality. Gene- and pathway-based results were compared to findings in an independent cohort of 479 sepsis patients with 28-day mortality data. Thirty-day mortality in the enrolled sepsis cohort was 37% (60 of 161 patients). We identified 1106 differentially expressed genes in nonsurvivors (Benjamini-Hochberg-adjusted P-value <.05), including several neutrophil-related genes (CEACAM8, ELANE, PRTN3, MPO, CEACAM6, DEFA4, MS4A3) with expression levels over 1.8 times higher in nonsurvivors despite adjusting for neutrophil counts. The neutrophil degranulation pathway was prominent based on its overrepresentation in (1) differentially expressed genes in both cohorts, (2) overrepresentation by gene set enrichment analysis, and (3) 4 of the 6 gene co-expression groups correlated with sepsis mortality. Our findings highlight the involvement of neutrophil degranulation genes in sepsis mortality, prompting further study to better understand whether they constitute a modifiable target.
Hu Y, Wang Y, Ren C
… +8 more, Liu S, Huang R, Sun T, Zhao Z, Duan Z, Yin J, Jiang T, Tan L
Am J Respir Cell Mol Biol
· 2026 Jun · PMID 41738275
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The vacuolar H+-ATPase (V-ATPase) is an enzymatic complex responsible for pumping H+ into the cytosol, thereby maintaining intracellular pH; however, its role in acute lung injury (ALI)/acute respiratory distress syndrom...The vacuolar H+-ATPase (V-ATPase) is an enzymatic complex responsible for pumping H+ into the cytosol, thereby maintaining intracellular pH; however, its role in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is unclear. In this study, the functional relevance of V-ATPase and hypoxia inducible factor (HIF) 1 were assessed using alveolar-specific ATP6V0C knockout mice (Atp6v0cAT2-KO) and HIF1A knockout mice (Hif1aAT2-KO), respectively. ATP6V0C expression levels were measured in serum and bronchoalveolar lavage fluid (BALF) of patients with ARDS. ATP6V0C expression was increased in lung tissues from ALI murine models and BALF from patients with severe ARDS. Genetic deficiency of ATP6V0C in alveoli attenuated the functional, histologic, and inflammatory hallmarks of lipopolysaccharide (LPS)-induced ALI but did not alter the host's susceptibility to bacterial pathogens. Mechanistically, transcriptomic analyses revealed that ATP6V0C-regulated genes are highly enriched in the HIF-1 signaling pathway. HIF-1α was upregulated synchronously with ATP6V0C in injured lungs, while co-immunoprecipitation confirmed their interaction. Following LPS instillation, the signs of ALI were further exacerbated in Hif1afl/fl mice pretreated with lung epithelial tropic adeno-associated virus carrying ATP6V0C, but not in Hif1aAT2-KO mice. HIF-1α, as a transcriptional factor, in turn, regulated ATP6V0C expression, forming a positive feedback loop. ATP6V0C levels were increased in BALF but not serum in patients with ARDS. ATP6V0C levels in BALF correlate with ARDS severity. In summary, our study identified an ATP6V0C-HIF-1α detrimental feedback loop that exacerbates epithelial apoptosis and inflammation, thereby driving the progression of ALI. Targeting the ATP6V0C-HIF-1α loop may hence present a promising therapeutic strategy against ALI/ARDS.
Reza MI, Tandberg C, Kumar A
… +6 more, Balraj P, Thompson MA, Prakash YS, Pabelick CM, Britt RD, Sathish V
Am J Respir Cell Mol Biol
· 2026 Jul · PMID 41738274
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In asthma, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα) drive excessive mitochondrial fission in ASM cells through activating dynamin-related protein 1 (DRP1). Recently, we demonstrated that aryl...In asthma, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα) drive excessive mitochondrial fission in ASM cells through activating dynamin-related protein 1 (DRP1). Recently, we demonstrated that aryl hydrocarbon receptor (AhR) is expressed in human ASM and is upregulated during inflammation and asthma. This study explores the role of AhR in regulating mitochondrial fission in human ASM cells under pro-inflammatory and asthmatic conditions. Primary human nonasthmatic and asthmatic ASM cells were treated with 6-formylindolo[3,2-b]carbazole (FICZ: AhR agonist), with or without TNFα. Mitochondrial morphology was assessed using MitoTracker staining. DRP1 expression was evaluated in whole-cell and mitochondrial fractions. Loss- and gain-of-function studies (AhR inhibition, knockdown, and overexpression) were performed. AhR binding on the DRP1 promoter and promoter activity were assessed by ChIP-qPCR and luciferase reporter. The effects of AhR activation on oxygen consumption rate (OCR) were analyzed using seahorse XF-Pro. AhR activation significantly inhibited TNFα- and asthma-induced mitochondrial fission in ASM cells via inhibiting DRP1 in both inactive and active forms. In contrast, AhR inhibition or knockdown aggravated mitochondrial fission, while AhR overexpression failed to prevent TNFα-induced fission without ligand activation. Mechanistically, AhR bound the DRP1 promoter and suppressed its promoter activity, consistent with a genomic mode of action, while failing to alter ERK1/2 phosphorylation. Additionally, AhR activation also reduced TNFα- and asthma-induced increase in OCR. Collectively, this study shows that AhR activation prevents mitochondrial fission by inhibiting DRP1 in ASM during inflammation and highlights AhR as a promising therapeutic target for asthma and other airway diseases associated with mitochondrial dysfunction.
Posham L, Wisler J, Gowdy KM
… +3 more, Pei D, Christman JW, Karpurapu M
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 41738270
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Extracellular vesicles (EVs) are increasingly recognized as critical mediators of intercellular communication, transferring a diverse repertoire of proteins, nucleic acids, and bioactive lipids that modulate the function...Extracellular vesicles (EVs) are increasingly recognized as critical mediators of intercellular communication, transferring a diverse repertoire of proteins, nucleic acids, and bioactive lipids that modulate the functional phenotype of recipient cells in both paracrine and endocrine manner. While the roles of EV-transported microRNAs (miRs) and proteins in pulmonary diseases have been extensively studied, the contribution of EV-encapsulated bioactive lipid mediators to the pathophysiology of pulmonary disorders, including acute respiratory distress syndrome (ARDS), remains largely underexplored. Here, we review the biosynthesis of bioactive lipids, their incorporation into EVs, and their roles in regulating pulmonary inflammation, injury, and resolution. We first highlight upstream signaling pathways, such as toll-like receptor 4 (TLR4) and the nuclear factor of activated T-cells cytoplasmic member 3 (NFATc3), which regulate the expression of lipid biosynthetic enzymes. We then examine how EV-encapsulated pro-inflammatory and pro-resolving lipids contribute to ARDS pathogenesis and clinical outcomes. Evidence supporting the role of EV-transported pro-resolving lipid mediators as key regulators of inflammation resolution and restoration of pulmonary homeostasis is also reviewed, along with their therapeutic potential in mitigating ARDS. Finally, we identify critical gaps in our understanding of how EV lipids modulate ARDS pathophysiology and discuss the challenges and opportunities for therapeutic targeting.
Yamamoto S, Wilson CL, Krueger MA
… +2 more, Gharib SA, Schnapp LM
Am J Respir Cell Mol Biol
· 2026 Jun · PMID 41738268
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Mannose receptor C type 2 (MRC2) is highly expressed in the lung and is the major endocytic receptor for the internalization and degradation of collagen in mesenchymal cells. Using Mrc2 knockout (KO) mice, we previously...Mannose receptor C type 2 (MRC2) is highly expressed in the lung and is the major endocytic receptor for the internalization and degradation of collagen in mesenchymal cells. Using Mrc2 knockout (KO) mice, we previously showed that MRC2 is required for efficient clearance of collagen in bleomycin-induced fibrosis. However, MRC2 also interacts with various cell-surface receptors and ligands beyond collagens, indicating that MRC2 may have additional, previously unrecognized functions in fibroblasts. To uncover novel pathways regulated by MRC2, we took an unbiased approach to compare the transcriptomic profile of MRC2-deficient lung fibroblasts to WT after in vitro culture. RNA-seq analysis revealed upregulation of the expression of several extracellular matrix genes but unexpectedly showed changes in expression of several cell cycle genes, including that encoding Forkhead box M1 (FOXM1), a key regulator of cell cycle progression, and enrichment of pathways involved in mitosis and cell division. Both in vitro and in vivo functional assays demonstrated that a greater proportion of MRC2-deficient lung stromal cells progress through the cell cycle more rapidly than WT cells, thereby accelerating overall proliferation. Inhibitor experiments showed that actively proliferating Mrc2 KO fibroblasts are more reliant on FOXM1 activity compared with WT cells, suggesting that FOXM1 is a critical mediator in fibroblast proliferation in the absence of MRC2. Our findings point to an unexpected role for this endocytic receptor in the regulation of lung stromal cell proliferation.
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 41738266
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Offspring asthma has emerged as a significant yet underexplored consequence of maternal obesity. This review synthesizes evidence from human and animal studies linking maternal obesity to increased asthma risk in offspri...Offspring asthma has emerged as a significant yet underexplored consequence of maternal obesity. This review synthesizes evidence from human and animal studies linking maternal obesity to increased asthma risk in offspring. We examine potential mechanisms, including impaired fetal lung development, epigenetic modifications, microbiome alterations, and metabolic dysregulation. A dedicated section focuses on the novel role of insulin signaling in the developmental programming of airway hyperresponsiveness, as insulin resistance-and the resulting hyperinsulinemia-is common in offspring of obese mothers. By integrating current findings and identifying key research gaps, this review outlines future directions to advance understanding and mitigation of maternal obesity's impact on offspring respiratory health.
Jiménez-Garcia L, Pérez-Montero A, Herranz S
… +8 more, Luque A, Tarín C, Castillo D, Lopez-Vilaro L, Mariñas-Pardo L, McCarthy C, Acebo P, Hortelano S
Am J Respir Cell Mol Biol
· 2026 Jun · PMID 41738246
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The alternative reading frame (ARF) protein, encoded by the CDKN2A locus, is well-recognized for its role in tumor suppression. Emerging evidence has highlighted ARF as a critical regulator of innate immunity and inflamm...The alternative reading frame (ARF) protein, encoded by the CDKN2A locus, is well-recognized for its role in tumor suppression. Emerging evidence has highlighted ARF as a critical regulator of innate immunity and inflammation, with links to increased susceptibility to cardiometabolic diseases. This study investigates the role of ARF in lung homeostasis and reveals that its deficiency in mice affects lipid metabolism and leads to pulmonary abnormalities resembling pulmonary alveolar proteinosis (PAP). ARF-deficient mice exhibited abnormal surfactant clearance, characterized by lipid and protein accumulation in the alveoli, foamy alveolar macrophages (AMs) with enlarged and vacuolated morphology, and increased bronchoalveolar lavage fluid turbidity. These changes were linked to disrupted surfactant homeostasis resulting from an imbalance between increased lipid uptake (via upregulation of scavenger receptors such as SR-A1 and CD36) and impaired lipid efflux, evidenced by reduced expression of the cholesterol transporter SR-BI. These mice also display reduced AM numbers, increased eosinophil and neutrophil infiltration, consistent with secondary PAP. Additionally, a distinctive chemokine and cytokine profile (elevated Ccl12, Ccl2, Cxcl1, and IL-10) was observed, which may be associated with type 2 immune responses and alternative AM polarization. Interestingly, ARF deficiency also appears to compromise AM maintenance through effects on self-renewal and survival. Pulmonary function tests revealed increased tissue elastance and damping, suggesting early-stage lung stiffness. Collectively, these findings highlight the essential role of ARF in lung homeostasis and lipid regulation, providing insights into its potential involvement in PAP pathogenesis.
Jing X, Wang Y, Roethle M
… +13 more, Jia S, Teng M, Konduri GG, Hessner MJ, Pritchard KA, Day BW, Jin Y, Ma X, Naylor S, Lin CW, Gu H, Du J, Teng RJ
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 41738245
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Metabolic dysregulation is implicated in the development of bronchopulmonary dysplasia (BPD). Taurine is an essential amino acid and a critical molecule in oxidative phosphorylation that mechanistically modulates angioge...Metabolic dysregulation is implicated in the development of bronchopulmonary dysplasia (BPD). Taurine is an essential amino acid and a critical molecule in oxidative phosphorylation that mechanistically modulates angiogenesis. Using a neonatal hyperoxia model supported by metabolomic and single-cell RNA-seq analyses, we showed that insufficient taurine contributes to alveolar simplification in BPD. To model BPD, Sprague-Dawley rat pups were exposed to > 90% oxygen. Plasma and lungs were obtained for multiomics. Pups received tunicamycin or tauroursodeoxycholic acid to study mechanisms that modulate taurine metabolism. Taurine was administered as rescue therapy after identifying its depletion in the lungs of BPD rats. Genes and proteins of oxidative phosphorylation were enriched in BPD rat lungs, whereas complex I (C-I) activity was paradoxically decreased. The reduction of taurine and taurine-dependent C-I core subunits, NADH Dehydrogenase Subunits 5 and 6 (ND5 and ND6), in BPD rat lungs explains this C-I paradox. The accompanying increase of plasma taurine in BPD rat pups indicates a decreased taurine transport, which can be explained by the reduced glycosylation and increased degradation of the taurine transporter. The results of complementary treatments, tunicamycin and tauroursodeoxycholic acid, indicate that endoplasmic reticulum stress contributes to the impaired taurine transport in BPD rat lungs. Taurine treatment increased the expression of ND5 and ND6, the percentage of proliferating general capillary endothelial cells, and alveolar complexity in BPD lungs. Our integrated metabolomic and single-cell analyses reveal that taurine enhances endothelial resilience primarily by activating the unfolded protein response rather than through direct angiogenic signaling. This represents a distinct antioxidant mechanism not previously characterized in hyperoxic lung injury.
Alt P, Müller I, Kiefmann M
… +5 more, Gudermann T, Kuebler WM, Griese M, Staab-Weijnitz CA, Dietrich A
Am J Respir Cell Mol Biol
· 2026 Jul · PMID 41738221
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Lung surfactant not only reduces surface tension at the air-liquid interface (ALI), but is also involved in pulmonary host defense. This important role in innate immunity of the respiratory tract is primarily mediated by...Lung surfactant not only reduces surface tension at the air-liquid interface (ALI), but is also involved in pulmonary host defense. This important role in innate immunity of the respiratory tract is primarily mediated by surfactant proteins A and D (SP-A, SP-D), which are secreted from alveolar epithelial type 2 (AT2) cells and from tracheal and bronchial epithelial cells expressing transient receptor potential vanilloid 4 (TRPV4) channels. In a mouse model deficient in TRPV4 (TRPV4-/-), reduced levels of SP-A and SP-D were detected in the bronchoalveolar lavage fluid. Production of both proteins in TRPV4-/- AT2 cells was not different to wild-type control cells, but secretion of SP-A and -D was impaired both in TRPV4-deficient murine AT2 and murine tracheal epithelial cells cultured at the ALI. In a translational approach, we established a human ALI model and differentiated bronchial basal cells to a pseudostratified epithelium. Downregulation of Trpv4 mRNA expression by specific siRNAs also resulted in a reduction of secreted SP-A levels. Interestingly, differentiation of basal cells to ciliated cells, but not club cells, which secrete SP-A and SP-D, was decreased after downregulation of TRPV4. Our data highlight novel essential functions of TRPV4 channels in secretion of SP-A and SP-D, which are important not only for innate immunity, but also for lung diseases like asthma and idiopathic pulmonary fibrosis.
Shemesh A, Carter S, Hays SR
… +3 more, Singer JP, Greenland JR, Calabrese DR
Am J Respir Cell Mol Biol
· 2026 Jun · PMID 41738213
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Lung transplantation prolongs survival for many patients with end-stage lung diseases, though long-term outcomes are limited due to allograft inflammation leading to chronic rejection. In this study, we aimed to identify...Lung transplantation prolongs survival for many patients with end-stage lung diseases, though long-term outcomes are limited due to allograft inflammation leading to chronic rejection. In this study, we aimed to identify the role of natural killer (NK) cell receptors in lung transplant recipient outcomes. We hypothesized that cystic fibrosis (CF) may be a model for systemic inflammation. Peripheral blood mononuclear cells were collected from recipients with CF (n = 6), recipients with chronic obstructive pulmonary disease (n = 6), and healthy donors (n = 7) for NK cell immunophenotyping via spectral flow cytometry and functional killing assays. Plasma B7H6 was also measured in 2 independent lung transplant cohorts to test the association with rejection. We identified a CF-specific reduction in NKp30 receptor expression, validated functionally against cells expressing the B7H6 ligand. The NKp30 reduction was not NK cell subset specific, suggesting a systemic influence. Further, we found that B7H6 in vitro reduced NKp30-mediated killing of target cells in a dose-dependent fashion. Analysis of soluble B7H6 concentrations in plasma revealed higher soluble B7H6 in CF recipients relative to other groups, suggesting a potentially broader role of soluble B7H6 in lung transplant outcomes. Consequently, B7H6 was higher in recipients without acute graft dysfunction, and higher B7H6 plasma concentrations conferred reduced risk of chronic lung allograft dysfunction (CLAD) and mortality. Single-cell RNA sequencing showed that B7H6 transcripts were most prevalent on ciliated airway epithelial cells and bronchoalveolar lavage monocytes and that airway B7H6 transcripts were reduced in CLAD. Thus, our data reveal a new role of the NKp30-B7H6 axis in potentiating lung allograft outcomes.
Gilbert RM, Jones DL, Wellmerling J
… +10 more, Caporarello N, Meridew JA, Choi KM, Haak AJ, Link PA, Tan Q, Lee JH, Ordog T, Ligresti G, Tschumperlin DJ
Am J Respir Cell Mol Biol
· 2026 Jul · PMID 41738205
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Repetitive injury is hypothesized to lead to progressive tissue fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to thi...Repetitive injury is hypothesized to lead to progressive tissue fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multimodal analyses on isolated lung mesenchyme during the initiation, progression, and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrotic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme exhibits an enhanced fibrotic program upon reinjury. We identify RUNX1 as a critical driver of both fibrotic activation and fibrotic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that RUNX1 is spontaneously activated in standard culture conditions, previously masking these roles of RUNX1. Targeted knockdown of RUNX1 dampens fibrotic mesenchymal cell activation immediately after cell isolation, but with reduced efficacy after only days of culture, confirming its functional importance to both early activation and long-term memory. Collectively, our findings implicate RUNX1 in the initiation and memory of fibrotic mesenchymal cell activation that together prime enhanced mesenchymal cell responses upon repeated injury.