Dey T, Zhyvylo I, Jiang L
… +11 more, Olapoju SO, Pena A, Avolio T, Lin D, Goncharov D, Greenland JR, Wolters PJ, DeLisser H, Pullamsetti SS, Kudryashova TV, Goncharova EA
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 40920996
·
Full text
HIPPO components mammalian Ste20-like protein kinases 1 and 2 (MST1/2) are well described growth suppressors. However, in pulmonary arterial hypertension (PAH), MST1/2 switch their roles and become pro-proliferative and...HIPPO components mammalian Ste20-like protein kinases 1 and 2 (MST1/2) are well described growth suppressors. However, in pulmonary arterial hypertension (PAH), MST1/2 switch their roles and become pro-proliferative and pro-survival molecules, supporting hyper-proliferation of pulmonary artery (PA) smooth muscle cells (PASMCs) and adventitial fibroblasts (PAAFs), remodeling of small PAs, and pulmonary hypertension. Here, we report that MST1/2 promotes hyper-proliferation and apoptosis resistance of human PAH PASMCs and PAAFs by up-regulating cell division cycle protein 20 (CDC20), establishing novel link between HIPPO-MST1/2 and cell cycle regulation in PAH.
Mukhitov AR, Evans JF, Han T
… +9 more, Ledwell OA, Rue R, Obraztsova K, Lin SM, Basil MC, Cantu E, Tang Y, Henske EP, Krymskaya VP
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 40920984
·
Publisher ↗
Lymphangioleiomyomatosis (LAM) is a rare lung disease caused by hyperactivation of the mTORC1 (mechanistic/mammalian target of rapamycin 1) growth pathway in a subset of mesenchymal lung cells. Histopathologically, LAM l...Lymphangioleiomyomatosis (LAM) is a rare lung disease caused by hyperactivation of the mTORC1 (mechanistic/mammalian target of rapamycin 1) growth pathway in a subset of mesenchymal lung cells. Histopathologically, LAM lesions have been described as immature smooth muscle-like cells that are positive for the immature melanocytic marker HMB45/PMEL/gp100 and phosphorylated ribosomal protein S6 (pS6). Advances in single-cell sequencing technology allowed us to group LAM cells according to their expression of cancer stem cell (CSC) genes and identify three clusters: a high CSC-like state (i.e., stem-like state), an intermediate state, and a low CSC-like inflammatory state. We show here that, in unique LAM cells, many extracellular matrix (ECM) genes, including collagens and CTHRC1 (collagen triple helix repeat-containing 1), are expressed in the high and intermediate CSC-like LAM clusters and suggest that, as is observed in CSCs, the ECM may provide a shield for LAM lesions against immunosurveillance. In LAM-associated fibroblasts, the bisteric mTORC1-selective inhibitor RMC-5552 blocked translation of TGF-β (transforming growth factor-β)-induced COL1A1, COL6A1, and phosphorylation of the mTORC1 substrates ribosomal protein S6K1/S6 (S6K1/ribosomal protein S6) and 4E-BP1/eIF4E (eukaryotic initiation factor 4E-binding protein/translation initiation factor 4E), whereas rapamycin, the U.S. Food and Drug Administration-approved therapy for LAM disease, inhibited only the S6K1/S6 axis. C82, a Wnt/β-catenin transcription inhibitor, prevented TGF-β-induced collagens but not pS6 or p4E-BP1. This demonstrates that mTORC1-driven 4E-BP1/eIF4E rapamycin-insensitive translational control overrides transcriptional control of ECM genes. Inhibition by RMC-5552 of ECM and fibroblast activation may result in destruction of CSC-like LAM cells and provide more enduring therapy for LAM.
Justeau G, Toigo M, Ribeiro Baptista B
… +20 more, Herath D, Yilmaz R, Crépin L, Abou Atmeh P, De Freitas Castro T, Alshehhi H, Poté N, Debrosse D, Mordant P, Truchi M, Mari B, Gagnadoux F, Audureau E, Al Alam D, El Mernissi K, Bertrand-Michel J, Derumeaux G, Boczkowski J, Dagouassat M, Boyer L
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 40920982
·
Publisher ↗
Emphysema is characterized by chronic alveolar destruction. Lipofibroblasts (LIFs) are crucial in the stem cell niche surrounding alveolar type II cells and may contribute to alveolar regeneration. We aim to determine wh...Emphysema is characterized by chronic alveolar destruction. Lipofibroblasts (LIFs) are crucial in the stem cell niche surrounding alveolar type II cells and may contribute to alveolar regeneration. We aim to determine whether emphysema is associated with LIF reduction and whether SREBP (sterol regulatory element-binding protein) activation promotes LIF differentiation and fibroblast stem cell niche properties. We quantified LIFs in the lungs of patients with emphysema compared with controls by costaining vimentin and ADFP (adipose differentiation-related protein). Using available datasets, we explored the expression level of lipogenic pathways in mesenchymal cells. Fibroblasts from patients were isolated, and SREBP-mediated signaling was activated with an LXR (liver X receptor) agonist, T0901317, and compared with rosiglitazone, a PPAR-γ (peroxisome proliferator-activated receptor γ) agonist (gene expression and lipidomic analysis). The stem cell niche properties of fibroblasts were evaluated through coculture with the H441 cell line or primary alveolar type II cells in organoid assays. Patients with emphysema had half as many LIFs as controls. T0901317 induced lipogenic differentiation of human lung fibroblasts and increased triglyceride contents and several phosphatidylcholine forms, particularly dipalmitoylphosphatidylcholine (PC32_0), one of the main surfactant components. Rosiglitazone increased only ADFP expression, with minor effects on lipid components. SREBP mediated signaling in fibroblasts and, to a lesser extent, PPAR-γ activation and increased their stem cell niche properties through the increase of organoid numbers. LIFs are decreased in the alveoli of patients with emphysema. Activation of SREBP-mediated signaling promotes lipogenic differentiation of fibroblasts and enhances their stem cell niche properties.
Imai Y, Kinugasa Y, Nukiwa R
… +14 more, Covarrubias MAL, Thwin KK, Yonezaki K, Shimizu T, Yamasaki S, Shintani Y, Hashimoto H, Suzuki Y, Fujino Y, Kubodera K, Kotani T, Furuyashiki T, Penninger J, Slutsky AS
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 40920972
·
Publisher ↗
Post-intensive care syndrome (PICS) is a serious condition involving physical weakness, depression, and cognitive impairment that develop during or after an ICU stay, often resulting in long-term declines in quality of l...Post-intensive care syndrome (PICS) is a serious condition involving physical weakness, depression, and cognitive impairment that develop during or after an ICU stay, often resulting in long-term declines in quality of life. Patients with acute respiratory distress syndrome and severe coronavirus disease (COVID-19) are at particularly high risk, yet the molecular mechanisms underlying PICS remain poorly understood. Here, we identify impaired Apelin-APJ signaling as a potential contributor to PICS pathogenesis through the disruption of interorgan homeostasis. Using a mouse model combining acute lung injury and hindlimb immobilization, we observed PICS-like features, including muscle atrophy, lung inflammation, and neurobehavioral abnormalities such as anxiety-like behavior and special working memory. Single-cell RNA sequencing in brain revealed upregulation of gene programs associated with Alzheimer's disease, depression, and neuroinflammation, particularly in endothelial cells and microglia. Concurrently, Apelin-APJ signaling was downregulated in skeletal muscle. These changes were exacerbated in Apelin-deficient mice and attenuated by muscle-specific Apelin overexpression, which also reduced systemic IL-6 and restored circulating Apelin levels. In survivors of ARDS who had severe COVID-19, ICU-acquired weakness was associated with reduced plasma Apelin and elevated IL-6 levels. Transcriptomic profiling of peripheral blood mononuclear cells from patients with ICU-acquired weakness showed gene expression signatures linked to depression and neurodegeneration, mirroring murine findings. These data suggest that impaired Apelin-APJ signaling may play a role in PICS pathophysiology. Although skeletal muscle appears to contribute to systemic Apelin levels, further studies are needed to clarify tissue-specific roles. Modulating this pathway could offer a therapeutic strategy to mitigate long-term outcomes in ICU survivors.
Cheng N, Kontodimas K, Matschulat A
… +2 more, Hicks-Berthet J, Varelas X
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 40920963
·
Full text
The increased presence of goblet epithelial cells in conducting airways of the respiratory system is common in pulmonary disorders and is often accompanied by disrupted immune and alveolar responses. Signaling effectors...The increased presence of goblet epithelial cells in conducting airways of the respiratory system is common in pulmonary disorders and is often accompanied by disrupted immune and alveolar responses. Signaling effectors that restrict goblet cell production include YAP and TAZ, transcriptional regulators of Hippo signaling, which repress goblet cell differentiation in the airway epithelium. Here, we investigated the acute responses to goblet cell metaplasia that are induced by the conditional loss of YAP/TAZ in club epithelial cells of adult mouse lungs. We found that the increased production of goblet epithelial cells drives inflammatory states broadly throughout airway and alveolar epithelial cells, including in distal alveolar type II (AT2) epithelial cells. We demonstrate that goblet cells produce factors that rapidly activate alveolar macrophages, which stimulate AT2 inflammatory responses, and that depletion of alveolar macrophages rescues AT2 responses to aberrant goblet cell production. These findings demonstrate direct roles for goblet cells in triggering inflammatory signals and reveal a circuitry of cellular communication that is initiated by mucus-producing cells in the lung.
Li Y, Zhou L, Li H
… +6 more, Sun G, Xu S, Tang X, Wan L, Zhang L, Tang M
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 40854083
·
Publisher ↗
Despite extensive transcriptomic alterations observed in tumors, the global landscape of isoform-level alternative splicing in cancer remains largely unexplored. Leveraging long-read sequencing, we successfully identifie...Despite extensive transcriptomic alterations observed in tumors, the global landscape of isoform-level alternative splicing in cancer remains largely unexplored. Leveraging long-read sequencing, we successfully identified and characterized full-length isoforms, together with tumor-specific splicing events in non-small-cell lung cancer (NSCLC). Our analysis identified 38,058 previously unannotated isoforms, which were subsequently validated using orthogonal multiomics datasets to confirm their transcriptional and translational activities. Notably, 269 splicing events were characterized as tumor specific, with 17 showing significant associations with NSCLC subtypes, while 13 were enriched across all NSCLC cases. Among these events, skipped exons in IFI27, PUF60, and ANAPC11, as well as an alternative first exon in YBEY, were absent from GENCODE annotations. These findings underscore the intricate complexity of isoforms and their clinical significance, particularly in terms of NSCLC subtype specificity and their potential as therapeutic targets. In conclusion, this study provides a valuable resource for the discovery of tumor-specific splicing targets in NSCLC, leveraging the unique advantages of long-read sequencing.
Thakur A, Clair G, Zhang L
… +3 more, Soni S, Mariani TJ, Çataltepe S
Am J Respir Cell Mol Biol
· 2026 Jan · PMID 40845320
·
Publisher ↗
Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects preterm infants. Disrupted microvascular growth is a well-recognized pathologic feature of BPD, which plays a critical role in arrested alveologenes...Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects preterm infants. Disrupted microvascular growth is a well-recognized pathologic feature of BPD, which plays a critical role in arrested alveologenesis. Recent studies have identified two subpopulations of pulmonary microvascular endothelial cells (ECs): general capillary (gCap) and aerocyte (aCap) cells. In this study, we validated proposed markers for gCap (GPIHBP1, PLVAP, CD93) and aCap (CA4, HPGD) at the protein level and investigated their abundance during late-stage lung development in murine and nonhuman primate (NHP) lungs. We also examined alterations in the abundance and proliferation of gCap and aCap cells in NHP and murine models of BPD. Our studies confirmed CA4 and HPGD as specific markers for aCap, and all three putative gCap markers were also detected in nonmicrovascular ECs. All markers except for HPGD showed a gradual increase in abundance during the saccular and alveolar stages of development in NHP lungs. In the NHP model of BPD, the abundance of both aCap markers and GPIHBP1 were decreased, whereas those of PLVAP and CD93 were increased. Additionally, there was an emergence of CA4+HPGD- aCap cells in BPD lungs. In late-stage control lungs, aCap proliferation was more robust than gCap proliferation, whereas no significant differences were observed between aCap and gCap proliferation rates in NHP BPD. Notably, in BPD lungs, gCap proliferation was more robust compared with control lungs. This study provides new insights into the distinct regulation patterns of microvascular ECs during lung development and neonatal lung injury in a translationally relevant NHP model.
Samarasinghe AE, Randell SH, Kulkarni HS
… +24 more, Weiser JN, Quinton LJ, Dickson RP, Mizgerd JP, Orihuela CJ, Parker D, Robinson KM, Prince AS, Evans SE, Kolls JK, Lee JS, Jeyaseelan S, Torres A, Miller LA, Hamilton DJ, Gómez MI, Moore BB, Walker RL, Barkal LJ, Hook JL, Lau GW, Sharma J, Witzenrath M, Dela Cruz CS
Am J Respir Cell Mol Biol
· 2025 Aug · PMID 40748059
·
Full text
The global incidence of respiratory infectious diseases caused by bacteria continues to increase, with acute lower respiratory tract infections contributing to significant morbidity and mortality. Preclinical models desi...The global incidence of respiratory infectious diseases caused by bacteria continues to increase, with acute lower respiratory tract infections contributing to significant morbidity and mortality. Preclinical models designed to investigate such respiratory bacterial diseases are of utmost importance to decipher their pathogenesis and develop novel targets for intervention and treatment. Animal models offer the powerful ability to investigate different pneumonia types at varying stages of infection and disease. However, the same models can promote important variations in outcome, potentially confounding scientific understanding in the field. Therefore, an expert panel was convened to deliberate best practices in animal models of bacterial pneumonia to identify validated methodologies and acknowledge limitations in the use of animal and non-animal models in this field of study. Herein, we summarize this American Thoracic Society workshop on animal models of bacterial pneumonia. This workshop further includes review of non-animal complementary or alternative models for studying bacterial pneumonia. Emphasis was placed on discussion of bacterial pathogens that frequently cause community- and hospital-acquired pneumonia, highlighting key aspects in modeling infection. Animal models discussed included small and large animals, based on their strengths. Finally and most importantly, the ethical considerations in the use of animal modeling for the study of bacterial lung infections was discussed. This workshop report is intended to provide insights to investigators in the field and may serve as a starting point for formal recommendations in the future.
Orlov M, Hara N, Rangarajan S
… +16 more, Jaramillo AM, Ye Q, Romo-Perez YM, Ngo K, NeeDell JC, Harder AQ, Jia F, Vestal B, Blumhagen RZ, Tu TH, McClendon J, McCubbrey AL, Smith BJ, Schwartz DA, Janssen WJ, Evans CM
Am J Respir Cell Mol Biol
· 2025 Dec · PMID 40737485
·
Full text
Minasenko B, Wang D, Chan J
… +8 more, Tran V, Gauthier TW, Marsit CJ, Jones DP, Go YM, Wongtrakool C, Su C, Hu X
Am J Respir Cell Mol Biol
· 2026 Jan · PMID 40737448
·
Full text
Prenatal exposure to cadmium (Cd) and arsenic (As) can severely impair fetal lung development, leading to lifelong adverse effects. As two of the most common and toxic heavy metals, Cd and As pose risks to many communiti...Prenatal exposure to cadmium (Cd) and arsenic (As) can severely impair fetal lung development, leading to lifelong adverse effects. As two of the most common and toxic heavy metals, Cd and As pose risks to many communities through food and water consumption. We have shown that prenatal coexposure to Cd and As at levels relevant to human intake inhibits branching morphogenesis, yet cell type-specific mechanisms remain elusive. Here, we examined early embryonic (Embryonic Day [E]12) lungs from mice exposed prenatally to either 0 (control) or 250 (treated) ppb of both Cd and As. Through single-cell multiome sequencing (single-cell transposase-accessible chromatin with high-throughput sequencing + single-cell RNA sequencing) and high-resolution metabolomics, we present a multifaceted landscape of Cd- and As-induced molecular and cellular disruption. We identified 19 cell states that exhibited state-specific changes in gene expression related to cell proliferation and differentiation. Velocity analysis integrating RNA splicing and chromatin kinetics showed profound disruptions in cell fate, particularly affecting differentiation of Sox2+ proximal progenitors and Wnt2+ mesenchymal progenitors. Gene regulatory network analysis pinpointed the diminished function of Gata6 and Gli2 as central to these disruptions, which was further confirmed by their reduced protein expression in exposed E12, E14.5, and E17 lungs. Additionally, metabolomic alterations in polyamine, tyrosine, and fatty acid biosynthesis correlated with changes in gene expression of catalytic enzymes. These findings demonstrate that Cd and As at levels relevant to human exposure impair early airway formation across multiple regulatory levels, including chromatin accessibility, transcription, and cell metabolism, and they provide insights into the factors central to cell resilience during this vulnerable stage of lung development.
Groves AM, Johnston CJ, Paris ND
… +6 more, Salama N, McGraw MD, Blanc R, Hernady E, Finkelstein J, Marples B
Am J Respir Cell Mol Biol
· 2026 Jan · PMID 40737367
·
Full text
Improvements in radiation therapy (RT) for thoracic cancers have increased survival; thus, preventing radiotoxicity in normal lung tissue becomes even more important. Respiratory infection is a lung stressor that increas...Improvements in radiation therapy (RT) for thoracic cancers have increased survival; thus, preventing radiotoxicity in normal lung tissue becomes even more important. Respiratory infection is a lung stressor that increases the risk of RT toxicity. However, this risk factor remains understudied with no effective treatment approaches. Although RT is toxic to tissue-resident alveolar macrophages, recruited monocyte-derived macrophages (MDMs) drive fibrogenesis. We therefore investigated how these macrophage populations are impacted by a respiratory infection subsequent to lung RT. Mice received whole-thorax RT (5-12.5 Gy), then were infected with influenza A virus (IAV) 1 or 20 weeks later. Chronic lung injury and acute and chronic macrophage responses were evaluated. RT plus IAV was lethal at doses that were well tolerated when either was administered singly. IAV potentiated chronic pathology from even a benign RT dose of 5 Gy, even when IAV was delayed for 20 weeks. Macrophage dynamics shifted toward more predominant proinflammatory, profibrotic MDM responses. Acutely, RT plus IAV amplified loss of tissue-resident alveolar macrophages but increased inflammatory MDMs. Expression of maturation receptors and antigen presentation factors by inflammatory MDMs decreased, whereas profibrotic factors increased. These novel findings warrant further investigation of the risks of respiratory infection for those receiving thoracic radiation.
Wang W, Chen S, Xi Z
… +6 more, Si Y, Liu Y, Chen J, Wang B, Zhu D, Gong L
Am J Respir Cell Mol Biol
· 2025 Dec · PMID 40720796
·
Full text
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, interstitial lung disease lacking an efficient drug to reverse it. Thus, there is an urgent need to elucidate the complex pathogenesis of IPF and identify ne...Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, interstitial lung disease lacking an efficient drug to reverse it. Thus, there is an urgent need to elucidate the complex pathogenesis of IPF and identify new therapeutic targets. It has been revealed that the pathophysiology of IPF is a highly orchestrated process that includes multiple cell types in which the contribution of endothelial cells (ECs) has attracted researchers' attention. However, although the involvement of ECs in fibrosis has been recognized, the underlying key molecules driving these changes are not well defined. In this study, we revealed that von Willebrand factor (VWF), a marker of damaged ECs, and endothelial dysfunction are positively correlated with IPF progression on the basis of reanalysis of gene expression profiles of patients with IPF. Next, we discovered that deficiency attenuated fibrosis in experimental models, including human cell lines () and mice (). Mechanistically, deficiency inhibited endothelial-to-mesenchymal transition, regulated vascular abnormalities, and limited M2 macrophage infiltration, which were achieved, at least in part, by the inhibition of Wnt signaling. Our findings provided evidence for the pivotal role of ECs in IPF and revealed that VWF might be a driving factor of endothelial-to-mesenchymal transition, suggesting that VWF can be developed as a potential therapeutic target against IPF.