American journal of physiology. Lung cellular and molecular physiology最新文献

{"title":"p53-miR-34a Feedback in Lung Fibroblasts Regulates Antifibrotic Effects of CSP7, Nintedanib and Pirfenidone.","authors":"Liang Fan, Rashmi S Shetty, Huy Minh Dao, Akarsha Balnadupete, Bharath Somasundram, Ashoka Kumar Bhagavath, Akhila Kongara, Hua Tang, Deborah E Citrin, Robert O Williams, Jay I Peters, Sreerama Shetty","doi":"10.1152/ajplung.00295.2024","DOIUrl":"10.1152/ajplung.00295.2024","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by progressive and irreversible loss of lung function. CSP7 exerts anti-fibrotic effects on fibrotic lung (myo)fibroblasts, which are the primary effector cells in progressive pulmonary fibrosis (PF) <i>via</i> restoring p53-microRNA-34a-feedback induction. However, p53-microRNA-34a's role in the anti-fibrotic effects of Nintedanib and Pirfenidone have not been explored. We compared the effects of oral-gavage-fed standard-of-care anti-fibrotic drugs, Nintedanib or Pirfenidone with CSP7 administered by intraperitoneal injection or <i>via</i> airway by dry powder inhalation against bleomycin induced PF using wild-type, p53 flox (p53^fl/fl), microRNA-34a flox (microRNA-34a^fl/fl) and tamoxifen inducible conditional knockout mice lacking p53 (p53^cKO) or microRNA-34a (miR-34a^cKO) expression in lung fibroblasts. Compared to wild-type or p53^fl/fl or microRNA-34a^fl/fl mice, p53^cKO and miR-34a^cKO mice exhibited more severe post-bleomycin body weight and lung function loss, lower survival, and more extracellular matrix deposition. Although daily treatment of wild-type mice with CSP7 or with Nintedanib or Pirfenidone between day 14-21 post-bleomycin improved survival, body weight and lung function, combination of CSP7 with Nintedanib or Pirfenidone was more effective than either drug. Interestingly, p53^cKO- and miR-34a^cKO-PF mice resisted these treatments, supporting the importance of restoration of p53-miR-34a-feedback induction in lung (myo)fibroblasts for the anti-fibrotic effects.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of hyperoxia and antibiotics on lung mesenchymal cells in experimental bronchopulmonary dysplasia.","authors":"Cathy van Horik, Joel Anne Meyboom, Anne Boerema-de Munck, Marjon J Buscop-van Kempen, Evelien Eenjes, Gabriëla G Edel, Demi Kortekaas, Rene Mh Wijnen, Wilfred F J van IJcken, Irwin K M Reiss, Robbert J Rottier, Jennifer J P Collins","doi":"10.1152/ajplung.00391.2024","DOIUrl":"10.1152/ajplung.00391.2024","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is the most common adverse outcome in preterm neonates, and a high risk for early-onset emphysema and asthma. BPD is characterized by disrupted alveolar and microvascular development, due to a variety of pathogenic factors, such as hyperoxia, inflammation and dysbiosis. The resulting clinical manifestations are challenging and current treatment options are limited. To improve therapeutic options, it is imperative to understand underlying causes. Resident lung mesenchymal stromal cells (L-MSCs) are important for alveolar microvascularization, repair and regeneration. Here, we report the immediate effects of hyperoxia and antibiotics-induced reduced bacterial load on L-MSCs and alveolar development using the hyperoxia-induced BPD mouse model. Newborn mice were exposed to hyperoxia from postnatal day 4 (P4) to P14, with room air recovery from P14 to P21. Dams received antibiotics-supplemented water (ampicillin, gentamycin and vancomycin) from E15 to P21. Hyperoxia significantly impaired alveolar development between P14 and P21, whereas both hyperoxia and antibiotics exposure impaired lung microvascular development. Moreover, hyperoxia reduced the number of pericytes, proliferative mesenchymal progenitors, <i>Col13a1</i>^POS matrix fibroblasts and P2RY14^POS alveolar myofibroblasts. RNA-Seq of LY6A-sorted L-MSCs revealed differential expression of 103 genes in hyperoxia, 10 of which are related to mast cell biology. Antibiotics exposure also altered mesenchymal cell distribution, suggesting an additional impact on lung development. The transcriptomic landscape and distribution of important L-MSC subtypes, and microvascular development are affected by hyperoxia and antibiotics exposure in a BPD-mouse model. In conclusion, we show that hyperoxia and antibiotics-induced reduced bacterial loadaffect the mesenchymal cell population, which may contribute to the development of BPD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of elexacaftor and bamocaftor on the metabolic and thermal stability of the F508del-CFTR protein in human airway epithelial cells.","authors":"Thomas Carrez, Sandra Mirval, Christine Barrault, Florian Devetter, Clarisse Vandebrouck, Frédéric Becq","doi":"10.1152/ajplung.00011.2025","DOIUrl":"https://doi.org/10.1152/ajplung.00011.2025","url":null,"abstract":"<p><p>Trikafta (elexacaftor/tezacaftor/ivacaftor, ETI) is approved for cystic fibrosis (CF) patients with at least one F508del mutation in the CFTR gene or another responsive mutation based on <i>in vitro</i> data. However, the pharmacological effects of ETI on F508del-CFTR remain incompletely defined in vitro. To explore the mechanisms underlying Trikafta's clinical efficacy, we used primary bronchial epithelial cells from F508del homozygous patients and CFBE41o- cells expressing F508del-CFTR. We assessed CFTR maturation, turnover, chloride transport, and thermal stability under various ETI concentrations and treatment durations at physiological temperature using electrophysiology (Ussing chamber, patch-clamp) and biochemical assays. We found that ETI efficacy on F508del-CFTR is strongly influenced by both treatment duration and concentration. Reducing ETI from standard doses, i.e. E (3 μM), T (18 μM), I (1 μM), to 33%, 11%, 3.3%, and 1.1% decreased function and maturation, but 33% retained most of the corrective effect. After 2 hours of treatment, around 50% of the CFTR-dependent current was preserved, unlike in untreated cells. Notably, replacing elexacaftor with bamocaftor further improved F508del-CFTR maturation and function compared to ETI, though it did not affect the rate of current decline over time. These findings highlight the importance of optimizing ETI dose and exposure duration, as both significantly affect F508del-CFTR stability and function. The retained efficacy at reduced concentrations suggests possible individualized dosing strategies, particularly for patients experiencing adverse effects with full-dose ETI.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low tidal volume ventilation facilitates spontaneous increase in bronchoconstriction and air trapping that can be resolved by deep inspiration and bronchodilator.","authors":"Yuto Yasuda, Geoffrey N Maksym, Lu Wang, Pasquale Chitano, Chun Y Seow","doi":"10.1152/ajplung.00085.2025","DOIUrl":"10.1152/ajplung.00085.2025","url":null,"abstract":"<p><p>Prolonged absence of deep inspiration (DI) increases airway resistance. The underlying mechanism is not entirely clear. We hypothesize that DI prohibition allows basal airway smooth muscle (ASM) tone to narrow and close airways over time, resulting in elevation of airway and lung resistance, as well as air trapping. We further hypothesize that DI or pharmacological bronchodilators can prevent or alleviate the resistance increase and air trapping. Physiological respiration was simulated in ex vivo sheep lungs. Lung resistance, elastance, and volume were measured using small tidal volume (120 mL), ventilation frequencies of 0.25 and 2 Hz, and transpulmonary pressure of 7.5 cmH₂O in the presence and absence of DI and bronchodilators. A DI maneuver, involving rapid inflation to total lung capacity followed by deflation to zero transpulmonary pressure, was used to resolve air trapping. Lung resistance and elastance were recorded pre- and post-DI. The experiments were also conducted in the presence of the bronchodilator salbutamol to assess the role of ASM. Ventilation without DI increased lung resistance and elastance, as well as air trapping. DI effectively resolved air trapping, restoring resistance and elastance to their initial values. Salbutamol also alleviated the increase in lung resistance, elastance, and air trapping. DI prevented air trapping and reduced lung resistance and elastance in ex vivo sheep lungs during tidal ventilation, playing a similar role as a pharmacological bronchodilator.<b>NEW & NOTEWORTHY</b> We showed that air trapping is a consistent feature in ex vivo sheep lungs possessing spontaneous bronchoconstriction, when the lungs are ventilated with small tidal volume without intermittent deep inspirations. We further demonstrated that in the presence of salbutamol, air trapping does not occur. This explains the importance of deep inspirations in normal breathing and indicates that airway smooth muscle tone could result in air trapping in the absence of deep inspiration.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L225-L233"},"PeriodicalIF":3.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lung-specific TGFβ overexpression increases airway fibrosis and airway contractility in transgenic mice.","authors":"Julia G Chitty, Maggie Lam, Weiyi Mao, Simon G Royce, Philip G Bardin, Jane E Bourke, Belinda J Thomas","doi":"10.1152/ajplung.00017.2025","DOIUrl":"10.1152/ajplung.00017.2025","url":null,"abstract":"<p><p>Transforming growth factor β1 (TGFβ1) is a pleiotropic cytokine implicated in the pathophysiology of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. Epithelial TGFβ1 is released in response to injury, inflammatory stimuli, and during bronchoconstriction to induce fibrosis. We hypothesized that elevated expression of endogenous TGFβ1, localized to the lung, would elicit autocrine effects to alter airway responsiveness. We utilized a transgenic mouse model of doxycycline (Dox)-induced, lung-specific overexpression of active TGFβ1 by giving Dox (0.25 mg/mL in drinking water, 8 wk), or normal water as a control. Comparing Dox with control groups, levels of TGFβ1 were ∼30-fold higher in bronchoalveolar lavage fluid (BALF), but not in serum, as measured by ELISA. BALF cells, predominantly macrophages, were ∼3.5-fold higher, with no evidence of tissue inflammation in hematoxylin and eosin (H&E)-stained sections from Dox mice. Higher collagen deposition was evident around the airways in Masson's trichrome-stained sections [subepithelial thickness (µm): control 10.4 ± 10.9, <i>n</i> = 9; Dox 25.8 ± 1.5, <i>n</i> = 13, <i>P</i> < 0.0001]. TGFβ1 overexpression increased baseline airway resistance and induced airway hyperresponsiveness (AHR) to methacholine (MCh) in vivo, as measured using in vivo plethysmography. Comparing precision-cut lung slices (PCLS) from separate Dox-treated and control mice, maximum contraction of intrapulmonary airways to MCh was increased ex vivo. Overall, elevated lung TGFβ1 levels resulted in localized airway fibrosis associated with increased airway contraction to MCh. These autocrine effects of endogenous TGFβ1 implicate its potential contribution to AHR, suggesting that targeting TGFβ1 may provide a novel approach to oppose excessive airway contraction in chronic lung diseases.<b>NEW & NOTEWORTHY</b> TGFβ upregulation is common in respiratory diseases. Here, the authors have utilized for the first time a mouse model of lung-specific overexpression of active TGFβ to demonstrate the dual role of TGFβ1 in structural remodeling and dysregulation of airway contractility. Given these pathologies are common to asthma and COPD, this model provides a unique opportunity to identify essential novel therapeutics for the treatment of chronic lung diseases.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L255-L265"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of pulmonary surfactant on lung fluid balance.","authors":"Gary F Nieman, Egidio Beretta, Joaquin Araos, Giuseppe A Miserocchi","doi":"10.1152/ajplung.00329.2024","DOIUrl":"10.1152/ajplung.00329.2024","url":null,"abstract":"<p><p>Karl von Neegaard's classic publication, in 1929, first identified the physiological function of pulmonary surfactant on alveolar mechanics. Dr. John Allen Clements brought this work to the clinic in the 1960s, culminating in the development of surfactant replacement therapy for infant respiratory distress syndrome (RDS). In this mini-review, we discuss pulmonary surfactants' role in maintaining lung fluid balance, which is essential in preventing pulmonary edema. Alveolar surface tension (γ) is transmitted into the perialveolar space surrounding pulmonary capillaries and corner vessels. Increasing surface tension at end expiration would increase alveolar recoil pressure and decrease alveolar radius, thus causing more subatmospheric pressure in the perialveolar space, generating an increased gradient for microvascular filtration. Studies have demonstrated a positive correlation between increased pulmonary extravascular water volume (PEWV) and high γ (γ = 8.3 ± 1.7 dyn/cm; PEWV = 3.4 ± 0.2 mL/g vs. γ = 23.2 ± 0.4 dyn/cm; PEWV = 6.1 ± 1.0 mL/g dry lung). A subsequent study demonstrated that the high γ did not increase capillary permeability, supporting the mechanism of high γ-induced pulmonary edema as a decrease in interstitial hydrostatic pressure. Computational modeling, as presented in our previous publications based on the Starling equation of fluid flux, identifies the impact of elevated alveolar surface tension on lung fluid balance. Loss of surfactant function favors fluid moving from the capillary across the endothelium into the perialveolar space and across the epithelium into the alveoli. We conclude that elevated alveolar surface tension plays a pivotal role in lung fluid balance and, if sufficiently elevated, can cause pulmonary edema even with normal capillary permeability.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L307-L314"},"PeriodicalIF":3.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining innovative methodologies with deep personal connections to further physiology research: lessons from Joseph D. Brain, ScD.","authors":"Jeffrey J Fredberg, Joseph P Mizgerd","doi":"10.1152/ajplung.00281.2024","DOIUrl":"10.1152/ajplung.00281.2024","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L197-L199"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrauterine inflammation-induced neonatal lung injury via succinic acid-mediated alveolar epithelial E-cadherin downregulation.","authors":"Baihe Li, Ze Chen, Dongting Yao, Wei Li, Qianqian Zhang, Meng Ni, Qianwen Shen, Zhenying Lin, Chunyu Cheng, Sudong Qi, Xiya Ding, Jiuru Zhao, Zhiwei Liu","doi":"10.1152/ajplung.00322.2024","DOIUrl":"10.1152/ajplung.00322.2024","url":null,"abstract":"<p><p>Intrauterine inflammation is associated with lung injury in offspring and long-term adverse pulmonary outcomes, but the underlying mechanism remains elusive. This study aimed to investigate the underlying molecular mechanism from the perspective of metabolites. Pregnant C57BL/6 mice received an intraperitoneal injection of LPS on <i>gestational day 12.5</i> to establish an intrauterine inflammation model. The results showed that prenatal LPS exposure induced bronchopulmonary dysplasia (BPD)-like alveolar simplification. Then, by LC/MS untargeted metabolomics analysis, succinic acid was found to be elevated in murine placentas and preterm human umbilical cord blood with intrauterine inflammation. Besides, the expression of succinate dehydrogenase B subunit (Sdhb), a key catalytic enzyme of succinic acid, was downregulated in the murine placentas with intrauterine inflammation. Tail intravenous administration of <i>Sdhb</i> siRNA led to the accumulation of succinic acid in the placenta and aggravated LPS-induced lung injury in the offspring. In offspring mice, intrauterine inflammation decreased E-cadherin levels in lung tissue, which were further reduced by <i>Sdhb</i> siRNA injection. Conversely, overexpression of E-cadherin alleviated inflammation-induced lung injury. In vitro experiments revealed that succinic acid downregulated E-cadherin expression in alveolar epithelial cells through the PI3K/Akt/Hif-1α pathway. Succinic acid also indirectly downregulated the E-cadherin expression in alveolar epithelial cells by inducing macrophage M2 polarization and the production of Tgf-β1. In conclusion, this study demonstrates that succinic acid is a critical mediator of intrauterine inflammation-induced lung injury in offspring.<b>NEW & NOTEWORTHY</b> Intrauterine inflammation induces the accumulation of succinic acid in the placenta, which subsequently downregulated E-cadherin expression in the alveolar epithelial cells, thereby contributing to lung injury.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L282-L295"},"PeriodicalIF":3.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirtuin 3 deficiency exacerbates emphysema and lung inflammation in a murine model of chronic obstructive pulmonary disease.","authors":"Taro Ishimori, Minako Saito, Masaaki Yuki, Mototaka Hattori, Masahiro Shuzui, Saki Nagoshi, Shiho Kono, Hideaki Isago, Hiroyuki Tamiya, Naoya Miyashita, Takashi Ishii, Yu Mikami, Takahide Nagase, Yasuhiro Terasaki, Yoichi Shinozaki, Akihisa Mitani","doi":"10.1152/ajplung.00212.2024","DOIUrl":"10.1152/ajplung.00212.2024","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a progressive lung disease caused mainly by cigarette smoke-mediated induction of oxidative stress. Sirtuin 3 (SIRT3) regulates reactive oxygen species levels, but there are no definitive reports on its role in COPD pathogenesis. We hypothesized that SIRT3 plays a protective role in COPD. First, we observed significantly reduced SIRT3 expression in COPD lungs and identified smoking as a suppressive factor for SIRT3 expression in the airway epithelium. Next, we analyzed the lung phenotypes of SIRT3 knockout (KO) mice and SIRT3-overexpressing transgenic (OE) mice, and induced a COPD model in these mice using elastase and lipopolysaccharide. We subsequently investigated the effects of SIRT3 on cytokine production, oxidative stress, and apoptosis in airway epithelial cells in vitro. SIRT3 knockout mice exhibited increased expression of apoptosis markers, and aged SIRT3 KO mice and SIRT3 KO COPD model mice exhibited a worsened emphysematous phenotype. By contrast, this effect was mitigated in SIRT3 OE COPD model mice. In vitro studies revealed that SIRT3 deficiency exacerbated inflammation, oxidative stress, and apoptosis in airway epithelial cells. We concluded that SIRT3 plays a vital role in COPD pathogenesis and could be a novel therapeutic target.<b>NEW & NOTEWORTHY</b> Our study is the first to elucidate the protective role of SIRT3 in the pathogenesis of COPD by modulating inflammatory responses and apoptosis. We have demonstrated that SIRT3 knockout mice spontaneously develop emphysema, and SIRT3 overexpression reduced elastase and LPS-induced emphysematous changes. In vitro studies have shown that SIRT3 deficiency leads to increased inflammation, oxidative stress, and apoptosis in airway and alveolar epithelium, contributing to the formation and exacerbation of emphysema.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L200-L213"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbonic anhydrase IX promotes acute lung injury and mortality in females during metabolic acidosis and pneumonia.","authors":"Reece P Stevens, Jacob Holston, Karam Maatouk, Chun Zhou, Madeline Stone, Viktoriya V Pastukh, C Michael Francis, Sagar Kumar, Meredith S Gwin, Sarah L Sayner, Troy Stevens, Ji Young Lee","doi":"10.1152/ajplung.00331.2024","DOIUrl":"10.1152/ajplung.00331.2024","url":null,"abstract":"<p><p>Carbonic anhydrase IX (CA IX) is a unique transmembrane CA isoform that is associated with chronic pulmonary vascular diseases and is upregulated in the lungs during infection. Whether CA IX contributes to alveolar-capillary dysfunction in the acute respiratory distress syndrome (ARDS) is unknown. Here, we tested the hypothesis that CA IX promotes acute lung injury during metabolic acidosis and pneumonia. Wild-type (WT) and CA IX knockout (KO) mice were fed 0.5% sucrose water (control) or 0.28 M NH₄Cl + 0.5% sucrose water for 7 days to induce metabolic acidosis, followed by intratracheal instillation of bacteria. Metabolic acidosis by itself did not cause pulmonary edema but modestly increased the lung wet-to-dry ratio in WT mice during pneumonia. A major sex difference in outcome was seen, where WT females had a higher filtration coefficient (<i>K</i>_f) in the isolated perfused lung and increased mortality compared with KO females. The <i>K</i>_f of WT and KO males did not differ; however, WT males had a 20% lower survival rate than KO males. In vitro expression of CA IX in pulmonary microvascular endothelial cells increased gap formation in the cell monolayer compared with KO cells during infection. No difference in lung bacterial clearance and plasma cytokines were seen between WT and KO mice regardless of sex. Thus, we report that CA IX promotes lung permeability and mortality but does not affect lung bacterial clearance, suggesting that CA IX may facilitate lung injury by directly affecting alveolar-capillary permeability and may serve as a therapeutic target in ARDS.<b>NEW & NOTEWORTHY</b> Acidosis is prevalent in patients with ARDS, yet the mechanisms involved in alveolar-capillary dysfunction during metabolic acidosis and lung injury remain poorly defined. Here, we report that carbonic anhydrase IX, a unique pH regulatory protein, promotes pulmonary edema and mortality but does not affect lung bacterial clearance during metabolic acidosis and pneumonia. Our findings suggest that carbonic anhydrase IX may serve as a therapeutic target to alleviate lung injury in patients with acidosis and ARDS.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L266-L281"},"PeriodicalIF":3.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}