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

{"title":"Early life oxidant pollutant exposure induces lung redox and RAAS dysregulation: Implications for innate immune responses.","authors":"Janice A Dye, Helen H Nguyen, Erica J Stewart, M C Schladweiler, Allen Ledbetter, Colette N Miller","doi":"10.1152/ajplung.00125.2025","DOIUrl":"https://doi.org/10.1152/ajplung.00125.2025","url":null,"abstract":"<p><p>The potential for early life air pollutant exposure to result in later onset respiratory disease in children and adults is an emerging public health concern. Fetal-growth-restriction (FGR) and childhood res-piratory infections are associated with impaired lung function in adulthood, and later in life, death from COPD. We previously showed that early gestational exposure of rats to the oxidant air pollutant, ozone, resulted in asymmetrical FGR and lung developmental delays. Herein, we investigate effects of early ges-tational, peri-adolescent, and combined ozone exposure on offspring health, lung injury, antioxidant reserve, and innate immune responses. Results revealed similar ozone effects in all offspring irrespective of exposure timing in terms of minor weight loss, reduced body temperature (1.5-2.0˚C), and moderate lung injury. Lung injury was inversely correlated with lung antioxidant capacity. Progeny of ozone-exposed dams (i.e., FGR-prone offspring) showed greater variability in ventilatory responses (EF₅₀, Penh) and increased Penh correlated with greater lung injury. FGR-prone offspring had more variable, often blunted immuno-inflammatory responses to subsequent ozone exposure. Enhanced expression for an-tioxidant (Nrf2-related or ARE) genes were observed in FGR-prone males, whereas decreased expression for hypoxia (Hif-related or HRE) and RAAS genes (<i>Ace</i>, <i>Agtr1</i>, <i>Ace2</i>) were observed in FGR-prone females, potentially suggesting that cross-talk between redox transcription factors, Hif/RAAS, NFκB, and Nrf2 led to differential responses. Collectively, these findings indicate that early life oxidant air pollutant exposure and resultant redox and RAAS dysregulation may impact <i>both</i> lung development and innate immune responses in a sex-dependent manner, effects that may increase vulnerability to respiratory infections.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243645","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":"SEX MODULATES THE VENTILATORY RESPONSE TO PASSIVE LIMB-INDUCED MUSCLE MECHANORECEPTOR ACTIVATION DURING HYPOXIA IN HUMANS.","authors":"Diogo Machado Oliveira, Talita M Silva, Tamires S Cesar, Ana Luiza C Sayegh, Bruno M Silva","doi":"10.1152/ajplung.00195.2025","DOIUrl":"https://doi.org/10.1152/ajplung.00195.2025","url":null,"abstract":"<p><p>Sex appears to modulate interactions between neural mechanisms involved in regulating pulmonary ventilation during mild hypoxic exercise. Therefore, we compared pulmonary ventilation responses elicited by isolated and combined stimulation of the carotid chemoreflex and muscle mechanoreflex between males and females. Twenty-eight healthy adults (14 females) underwent four experimental manipulations: 1) normoxic rest (no stimulation), 2) hypoxic rest (carotid chemoreflex stimulation), 3) normoxic passive movement (muscle mechanoreflex stimulation), and 4) hypoxic passive movement (reflexes costimulation). Isocapnia was maintained using a rebreathing system, and hypoxia was induced by breathing 12% oxygen. Passive movement involved 30-second bouts of unilateral knee manipulation at 300º/s, with surface electromyography confirming absence of voluntary muscle contractions. In males, the pulmonary ventilation response to passive limb movement (last 10 seconds change versus rest) was greater under hypoxia than normoxia (mean ± SD: hypoxia = 3.6 ± 2.0 vs. normoxia = 1.6 ± 2.4 L/min; P = 0.003), whereas no difference was observed in females (hypoxia = 1.9 ± 2.4 vs. normoxia = 2.2 ± 1.5 L/min; P = 1.000). Moreover, pulmonary ventilation remained elevated in males (hypoxia = 2.7 ± 2.4 vs. normoxia = -0.1 ± 2.2; P < 0.001) but not in females (hypoxia = 0.4 ± 3.3 vs. normoxia = 0.5 ± 1.5; P = 1.000), 30 seconds following passive limb movement under hypoxia. These findings support a synergistic carotid chemoreflex-muscle mechanoreflex interaction in males but not in females. The persistent ventilatory elevation post-stimulation indicates that short-term potentiation contributes to this synergistic interaction in males.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237798","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":"Dietary Influence on Lung Injury and Immune Modulation in Cadmium-Exposed Mice.","authors":"Chandrashekhar Prasad, Debolina Dasgupta, Aprajita Tripathi, Nicolas Steele, Santhosh Kumar Duraisamy, Kalyani Pyaram, Isaac Kirubakaran Sundar","doi":"10.1152/ajplung.00196.2025","DOIUrl":"https://doi.org/10.1152/ajplung.00196.2025","url":null,"abstract":"<p><p>Cadmium (Cd), a toxic heavy metal found in air pollution, poses serious risks to lung health due to its efficient pulmonary absorption and prolonged biological half-life. This study examines how ad-libitum (AL), time-restricted feeding (TRF), and intermittent fasting (IF) influence Cd-induced lung injury and immune responses in mice. Adult male C57BL/6 mice were pre-acclimated to AL, TRF, or IF regimens for three weeks, followed by intratracheal exposure to cadmium chloride (CdCl₂, 0.5 mg/kg). Lung mechanics were assessed using flexiVent, bronchoalveolar lavage (BAL) fluid was analyzed for inflammation, and immune profiling was performed on spleens and mediastinal lymph nodes (MLNs) 14 days post-exposure. Cd exposure increased immune cell infiltration in BAL fluid. IF mice showed significantly elevated inflammatory cytokines, while TRF mice had modest increases. Histological analysis revealed greater lung inflammation in TRF mice, whereas lung mechanics were more impaired in IF mice, suggesting distinct injury profiles. Immune profiling showed that IF reduced activated and effector T-cell populations in the spleen but increased them in MLNs, indicating a shift in immune localization. Furthermore, compared to the AL, Cd-exposed IF mice had minimal changes in T-cell distribution but reduced effector CD4⁺ and CD8⁺ T-cells in the spleen and increased in MLNs. In contrast, TRF mice exhibited minimal changes in T-cell distribution. These findings suggest that dietary regimens modulate immune responses and lung injury following Cd exposure. Feeding patterns play a critical role in shaping susceptibility to environmental toxicants and should be considered in future toxicological and immunological studies.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237755","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":"Mesenchymal stromal cell extracellular vesicles reduce <i>Pseudomonas</i> biofilm formation, and let-7b-5p loading confers additional anti-inflammatory effects.","authors":"Sharanya Sarkar, Roxanna Barnaby, Amanda B Nymon, Lily A Charpentier, Lily Taub, Matthew J Wargo, Daniel J Weiss, Tracey L Bonfield, Bruce A Stanton","doi":"10.1152/ajplung.00187.2025","DOIUrl":"10.1152/ajplung.00187.2025","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (<i>CFTR</i>) gene, leading to chronic pulmonary infections and hyperinflammation. Among pathogens colonizing the CF lung, <i>Pseudomonas aeruginosa</i> is predominant, infecting over 50% of adults with CF, and becoming antibiotic-resistant over time. Current therapies for CF, while providing tremendous benefits, fail to eliminate persistent bacterial infections, chronic inflammation, and irreversible lung damage, necessitating novel therapeutic strategies. Our group engineered mesenchymal stromal cell-derived extracellular vesicles (MSC EVs) to carry the microRNA let-7b-5p as a dual anti-infective and anti-inflammatory treatment. MSC EVs are low-immunogenicity platforms with innate antimicrobial and immunomodulatory properties, whereas let-7b-5p reduces inflammation. This study demonstrates that MSC EVs effectively blocked the formation of antibiotic-resistant <i>P. aeruginosa</i> biofilms on primary human bronchial epithelial cells (pHBECs), and let-7b-5p loading into MSC EVs conferred additional anti-inflammatory effects by reducing <i>P. aeruginosa</i>-induced IL-8 secretion by pHBECs. This approach holds promise for improving outcomes for people with CF, and future work will focus on optimizing delivery strategies and expanding the clinical applicability of MSC EVs to target other CF-associated pathogens.<b>NEW & NOTEWORTHY</b> This is the first study demonstrating that mesenchymal stromal cell extracellular vesicles (MSC EVs) block antibiotic-resistant <i>P. aeruginosa</i> biofilm formation and that let-7b-5p-loaded MSC EVs reduce inflammation in CF primary human bronchial epithelial cells.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L455-L469"},"PeriodicalIF":3.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022638","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":"Aerosolized vitamin D attenuates ozone-induced inflammation and transcriptional responses via membrane antioxidant effects in human bronchial epithelial cells.","authors":"Kevin D Schichlein, Syed Masood, Hye-Young H Kim, Benjamin J Hawley, Arunava Ghosh, James M Samet, Ned A Porter, Gregory J Smith, Ilona Jaspers","doi":"10.1152/ajplung.00233.2025","DOIUrl":"10.1152/ajplung.00233.2025","url":null,"abstract":"<p><p>Ozone exposure increases the risk of infection, worsens lung diseases, and causes systemic health issues. As ambient ozone levels continue to rise globally, effective interventions are needed to reduce these harmful effects. Vitamin D, known for its anti-inflammatory properties, has been inversely linked to various lung conditions, including ozone-induced airway inflammation and reduced lung function. However, oral vitamin D supplementation has shown inconsistent results, possibly due to poor delivery to lung tissues. This study explores a novel approach using vitamin D aerosols to counter ozone-induced damage in primary human bronchial epithelial cells. Cells were pretreated with vitamin D aerosols apically or as a bulk addition basolaterally before ozone exposure at the air-liquid interface. Both treatment routes significantly reduced the ozone-induced secretion of the inflammatory cytokine IL-8. Furthermore, vitamin D suppressed the ozone-induced expression of inflammation- and oxidative stress-related genes, including <i>CXCL8</i>, <i>FFAR2</i>, <i>PTGS2 (</i>COX-2<i>)</i>, and <i>NFKB2</i>. Gene set enrichment analysis indicated that vitamin D reversed ozone-driven pathways related to inflammation, oxidative stress, and immune dysfunction. In addition, vitamin D pretreatment reduced lipid peroxidation, glutathione oxidation, and formation of ozone-derived oxysterols, suggesting a membrane antioxidant effect. These findings support vitamin D's potential as a protective agent against inhaled oxidants and highlight inhaled delivery as a promising therapeutic strategy for treating lung diseases.<b>NEW & NOTEWORTHY</b> Vitamin D aerosols have the potential to protect against exposure to ozone and other inhaled oxidants and prevent the development and exacerbation of lung disease. Here, we show that aerosolized vitamin D treatment decreased ozone-induced oxidative stress and inflammatory responses, as well as decreased production of an oxysterol, β-epoxycholesterol, indicating vitamin D may act as a membrane antioxidant in the airway epithelium.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L514-L523"},"PeriodicalIF":3.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051561","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}

{"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 antifibrotic effects on fibrotic lung (myo)fibroblasts, which are the primary effector cells in progressive pulmonary fibrosis (PF) via restoring p53-microRNA-34a-feedback induction. However, p53-microRNA-34a's role in the antifibrotic effects of nintedanib and pirfenidone has not been explored. We compared the effects of oral-gavage-fed standard-of-care antifibrotic drugs, nintedanib or pirfenidone, with CSP7 administered by intraperitoneal injection or via 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 with 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 <i>days 14</i> and <i>21</i> 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 antifibrotic effects.<b>NEW & NOTEWORTHY</b> Pulmonary fibrosis is a progressive and fatal fibroproliferative disease. The current drugs (nintedanib/pirfenidone) only slow clinical progression. Myofibroblasts are the primary effector cells of PF. We found that CSP7, nintedanib and pirfenidone exert antifibrotic effects through restoring p53-microRNA-34a feedback induction in lung (myo)fibroblasts. We further found that daily treatment of mice with CSP7/nintedanib/pirfenidone between <i>days 14</i> and <i>21</i> post-bleomycin lung fibrosis improve survival, body weight and lung function, and combination therapy had added benefit.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L480-L498"},"PeriodicalIF":3.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519591/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CFTR-independent prostaglandin E₂-stimulated chloride secretion in human airway.","authors":"Shayda M Abazari, Ghazal Masarweh, Jesse Gammons, Jessica B Sarthi, Beate Illek, Zachary M Sellers","doi":"10.1152/ajplung.00279.2024","DOIUrl":"10.1152/ajplung.00279.2024","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Prostaglandin E&lt;sub&gt;2&lt;/sub&gt; (PGE&lt;sub&gt;2&lt;/sub&gt;) is a potent stimulator of airway epithelial Cl&lt;sup&gt;-&lt;/sup&gt; secretion. PGE&lt;sub&gt;2&lt;/sub&gt; can stimulate cystic fibrosis transmembrane conductance regulator (CFTR)-independent Cl&lt;sup&gt;-&lt;/sup&gt; secretion from Calu-3 submucosal gland cells, whereas human bronchial epithelial (HBE) cells require CFTR. The aim of this study is to determine the mechanism(s) driving CFTR-independent PGE&lt;sub&gt;2&lt;/sub&gt;-stimulated Cl&lt;sup&gt;-&lt;/sup&gt; secretion in Calu-3 cells. Short-circuit current (&lt;i&gt;I&lt;/i&gt;&lt;sub&gt;sc&lt;/sub&gt;) was measured in Calu-3, HBE, and duodenal enteroids in Ussing Chambers. mRNA expression and intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; (Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;i&lt;/sub&gt;) was determined by qPCR and Fura-Red imaging, respectively. In Calu-3 and HBE cells, PGE&lt;sub&gt;2&lt;/sub&gt;-stimulated &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;sc&lt;/sub&gt; was reduced by bilateral and basolateral-only removal of extracellular Ca&lt;sup&gt;2+&lt;/sup&gt; (Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt;), but not by inhibition of protein kinase A (PKA), inositol 1,4,5-triphosphate (IP&lt;sub&gt;3&lt;/sub&gt;), or Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;i&lt;/sub&gt; stores. Duodenal enteroids used PKA, IP&lt;sub&gt;3&lt;/sub&gt;, Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;i&lt;/sub&gt; and Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt;. EP receptor mRNA expression and functional measurements indicated EP4 receptor dominance in Calu-3 cells. EP4 receptor agonist CAY-10598 (CFTR&lt;sub&gt;inh&lt;/sub&gt;-172, glibenclamide) increased Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;i&lt;/sub&gt; and &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;sc&lt;/sub&gt; was driven by Ca&lt;sup&gt;2+&lt;/sup&gt;-activated Cl&lt;sup&gt;-&lt;/sup&gt; secretion. &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;sc&lt;/sub&gt; was inhibited by dasatinib, wortmannin, and GSK650394, indicating involvement of Src, phosphoinositol phosphate (PI3K), and serum glucocorticoid kinase 1 (SGK1). CFTR-independent CAY-10598-stimulated &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;sc&lt;/sub&gt; was mediated by apical Ca&lt;sup&gt;2+&lt;/sup&gt; release-activated Ca&lt;sup&gt;2+&lt;/sup&gt; channels (CRACs), P2X receptors, and basolateral TRPV channels. Calu-3 and HBE cells predominantly use EP4 receptors and Ca&lt;sup&gt;2+&lt;/sup&gt;&lt;sub&gt;e&lt;/sub&gt;-mediated signaling for PGE&lt;sub&gt;2&lt;/sub&gt;-stimulated Cl&lt;sup&gt;-&lt;/sup&gt; secretion. However, Calu-3 cells leverage apical Ca&lt;sup&gt;2+&lt;/sup&gt; entry through CRAC and P2X receptors, together with basolateral TRPV activation, Src, PI3K, and SGK1 signaling, for CFTR-independent Cl&lt;sup&gt;-&lt;/sup&gt; secretion. Gaining insights into means to increase CFTR-independent airway Cl&lt;sup&gt;-&lt;/sup&gt; secretion may identify novel therapies to help ameliorate lung diseases with compromised CFTR function.&lt;b&gt;NEW & NOTEWORTHY&lt;/b&gt; Identified that prostaglandin E&lt;sub&gt;2&lt;/sub&gt; uses EP4 prostanoid receptor-mediated activation of Src, phosphoinositol phosphate (PI3K), and serum glucocorticoid kinase 1 (SGK1) to stimulate cystic fibrosis transmembrane conductance regulator (CFTR)-independent, calcium-activated chloride secretion through apical calcium release-activated calcium channels, P2X receptors, and basolateral TRPV channels in Calu-3 submucosal gland airway cells. These findings provide new potential targets to bypass airway chloride secretory defects in lung diseases ","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L428-L439"},"PeriodicalIF":3.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599123","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, Joël Meyboom, Anne Boerema-de Munck, Marjon Buscop-van Kempen, Evelien Eenjes, Gabriela G Edel, Demi Kortekaas, Rene M H Wijnen, Wilfred F J van IJcken, Irwin 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 embryonic day 15 (E15) to P21. Hyperoxia significantly impaired alveolar development between P14 and P21, whereas both hyperoxia and antibiotic 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 sequencing (RNA-seq) of LY6A-sorted L-MSCs revealed differential expression of 103 genes in hyperoxia, 10 of which are related to mast cell biology. Antibiotic 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 antibiotic exposure in a BPD mouse model. In conclusion, we show that hyperoxia- and antibiotics-induced reduced bacterial load affect the mesenchymal cell population, which may contribute to the development of BPD.<b>NEW & NOTEWORTHY</b> Bronchopulmonary dysplasia (BPD) is associated with preterm-born children, and antibiotic treatment increases the incidence. Lung repair is affected in BPD, and here we focused on the LY6A^POS lung mesenchymal cells (L-MSCs), which modulate repair. We show that hyperoxia, which induces BPD in rodents, and antibiotics affect the transcriptome of these cells, resulting in altered signaling to mast cells. Antibiotics also affected the hyperoxia-induced changes in the cellular composition of L-MSCs at early alveologenesis.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L440-L454"},"PeriodicalIF":3.5,"publicationDate":"2025-10-01","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":"Airway sympathectomy attenuates inflammation, transcriptional ratios of Muc5ac and Muc5b, and airway mechanic deficits in mice delivered intranasal IL-13.","authors":"Pedro Trevizan-Baú, Amy L Fagan, Shanil P Amin, Leah R Reznikov","doi":"10.1152/ajplung.00139.2025","DOIUrl":"10.1152/ajplung.00139.2025","url":null,"abstract":"<p><p>Excessive mucus in the airways is an underlying pathological feature of many airway diseases, including asthma. Therapeutic options to reduce mucus production in the airways remain limited. One possible therapeutic target is the airway sympathetic nerves. Although lung sympathetic innervation has been considered sparse, sympathetic nerves secrete neurotransmitters that act on adrenergic receptors, including β₂-adrenergic receptor (β₂AR). Interestingly, in experimental models, chronic use of β₂AR agonists can augment mucus secretion. Thus, in the present study, we tested the hypothesis that airway sympathetic nerves regulate mucus production in the airway in response to the type 2 cytokine interleukin 13 (IL-13). We performed airway sympathectomy using intranasal instillation of the synthetic neurotoxin 6-hydroxydopamine (6-OHDA). Airway sympathectomy attenuated multiple IL-13-mediated airway deficits, including density of goblet cells containing neutral mucins, transcriptional ratio of mucin 5ac (Muc5ac) to mucin 5b (Muc5b), and airway elastance and tissue damping. Although total <i>Muc5ac</i> and <i>Muc5b</i> transcript levels and Muc5ac and Muc5b protein levels in bronchoalveolar lavage were not significantly altered, these changes suggest that airway sympathectomy modifies goblet cell phenotype and mucin composition. Airway sympathectomy also dampened IL-13-mediated increases in total lung transcripts important for regulating allergic responses, including interleukin 6, complement component 3, and colony-stimulating factor. This study reveals that airway sympathetic nerves regulate physiologic, molecular, and inflammatory responses to type 2 (IL-13-mediated) airway inflammation and raises the possibility that they may serve as potential targets for therapeutic intervention.<b>NEW & NOTEWORTHY</b> The role of airway sympathetic nerves in regulating airway responses remains largely undefined. We demonstrated that chemical depletion of airway sympathetic nerves attenuates specific IL-13-induced airway deficits at the molecular, cellular, and functional level. Our data suggest that airway sympathetic nerves may represent novel therapeutic targets to alleviate some pathologic features due to type 2 (IL-13-mediated) airway inflammation.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L524-L537"},"PeriodicalIF":3.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051570","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":"Mechanisms of lung crosstalk with end organs: scientific session V-ReSPIRE 2025.","authors":"Navneet Singh, Ceren Koçana, Eric P Schmidt, Mark L Hepokoski, Michael A Matthay, Troy Stevens","doi":"10.1152/ajplung.00175.2025","DOIUrl":"10.1152/ajplung.00175.2025","url":null,"abstract":"<p><p>Session V of the inaugural biennial Research Symposium on Pulmonary Injury and Repair of the Endothelium showcased cutting-edge research on pulmonary endothelial crosstalk with end organs and its role in vascular disease. Growing evidence suggests that communication between injured organs and distal vascular beds plays a critical role in the pathogenesis of complex conditions such as sepsis, acute respiratory distress syndrome, pulmonary arterial hypertension, and heart failure with preserved ejection fraction. Circulating mediators-including heparan sulfate fragments, proinflammatory cytokines, mitochondrial damage-associated molecular patterns, bone morphogenetic protein 9, bile acids, and nitric oxide-have emerged as key factors linking pulmonary endothelial dysfunction to neural impairment, acute kidney injury, subclinical liver injury, and left-sided heart disease. This review highlights recent advances in the field, identifies critical knowledge gaps, and outlines future research directions aimed at elucidating mechanisms of multiorgan dysfunction and identifying novel therapeutic targets.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L419-L427"},"PeriodicalIF":3.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938896","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}