Comprehensive Physiology最新文献

{"title":"Loss of Y Chromosome Associates With Lung and Cardiac Dysfunction in COPD.","authors":"Chanil Valasarajan, Tina Rasper, Jochen Wilhelm, Deepesh Dhakad, Stefan Kuhnert, Werner Seeger, Stefanie Dimmeler, Robert Bals, Rajkumar Savai, Ali Önder Yildirim, Andreas Zeiher, Soni Savai Pullamsetti","doi":"10.1002/cph4.70142","DOIUrl":"10.1002/cph4.70142","url":null,"abstract":"<p><p>This study highlights the previously unknown association of mosaic loss of the Y chromosome to impaired gas exchange and cardiac dysfunction, implicating mosaicism in immune-mediated, multi-organ decline and revealing a mechanistic basis for sex-biased vulnerability in COPD.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70142"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608247","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":"Heart-Lung Interactions in Gas Exchange: From Physiology to Pathophysiology.","authors":"Giuseppe Miserocchi, Egidio Beretta","doi":"10.1002/cph4.70149","DOIUrl":"10.1002/cph4.70149","url":null,"abstract":"<p><p>This review outlines the physiological organization of heart-lung coupling that ensures efficient gas exchange. Subsequently, factors that compromise this efficiency are examined. The development of perturbation in lung fluid balance, originating from both capillary and alveolar sources, is discussed in detail, as it represents a frequently overlooked contributor to impaired gas exchange. Intrinsic mechanisms by which the lung resists edema formation are then presented. We provide a quantitative functional model based on physical principles to describe the diffusion-perfusion interaction in the air-blood barrier aiming to interpret several pathological conditions, including pulmonary fibrosis, lung resection, heart failure syndromes, and mechanically ventilated patients with acute hypoxemic respiratory failure (AHRF).</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70149"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13090562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716134","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":"The Cardiac Circadian Clock Regulates Rhythms in Peripheral Tissues via Fibulin 5.","authors":"Sharanya S Bettadapura, David C Tangeman, Sushumna B Satyanarayana, Madison M Ruhmann, Willa J Bonds, J Harrison Edwards, Pooja Gupta, Aykhan Yusifov, William D Todd, Danielle R Bruns","doi":"10.1002/cph4.70147","DOIUrl":"10.1002/cph4.70147","url":null,"abstract":"<p><p>Research to date describes the suprachiasmatic nucleus (SCN) of the hypothalamus as the master pacemaker that synchronizes circadian rhythms in peripheral tissues. However, recent high-impact studies demonstrate that non-SCN tissues can also coordinate rhythms in other peripheral tissues. However, the extent to which the cardiac clock regulates peripheral clocks has not yet been tested. Therefore, we investigated the role of the cardiac clock in modulating extra-cardiac circadian function using a model of cardiac-specific deletion of the core clock protein Bmal1 (Bmal1 cKO). Bmal1 cKO mice demonstrated attenuated day-night differences in skeletal muscle core clock gene expression (Bmal1, Clock, Per1) and circadian expressed metabolic genes (Pdk4, Ppara) as well as impaired day-night muscle grip strength. In the kidney, Bmal1 cKO mice had blunted core clock gene and water balance gene expression (Avp) compared to WT mice. Proteomic analysis of serum identified fibulin 5 (Fbln5) as a potential cardiokine mediating peripheral circadian effects, with rhythmic expression of Fbln5 disrupted in the heart and serum of Bmal1 cKO mice compared to WT. Exogenous treatment of synchronized C2C12 myotubes and human renal cells with rFbln5 disrupted rhythmic clock gene expression. In vivo, supplementation of Fbln5 in the drinking water of healthy wildtype C57Bl6 mice also disrupted kidney muscle rhythms. RNA sequencing data suggested that Fbln5 alters circadian output programs via stress-activated mechanotransduction and metabolic remodeling. Importantly, these changes occur without overt SCN dysfunction. Together, we demonstrate a critical role for the heart in regulating peripheral circadian control through the novel circadian cardiokine Fbln5.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70147"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13078729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147671184","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":"The Importance of Liver-Lung Communication in Pulmonary Vascular Diseases.","authors":"Navneet Singh, Hilary M DuBrock, Sasha Z Prisco, Zhiyu Dai, Qi Zheng, Michael B Fallon, Thenappan Thenappan, Corey E Ventetuolo, Arun Jose","doi":"10.1002/cph4.70140","DOIUrl":"10.1002/cph4.70140","url":null,"abstract":"<p><p>In normal health, the liver and lungs enjoy a close anatomic, physiologic, and functional relationship. In the context of pulmonary vascular disease, however, there is accumulating evidence that the interplay between the gut microbiome, hepatic system, and pulmonary vasculature (so-called \"gut-liver-lung\" axis) plays an important role in driving disease pathogenesis and determining clinical outcomes. Despite recognizing the importance of the gut-liver-lung axis in pulmonary vascular disease however, little is known about the clinical characteristics, circulating factors, and physiologic pathways that mediate this important axis of communication. In this clinical and translationally focused review, we provide an overview of liver-lung communication in normal physiology, and contrast this with gut-liver-lung derangements in pulmonary arterial hypertension, portopulmonary hypertension, and hepatopulmonary syndrome. We conclude with identifying key gaps in knowledge that will need to be addressed in order to manipulate the gut-liver-lung axis to prevent worsening pulmonary vascular disease, develop novel therapeutics, and improve patient outcomes.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70140"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13039249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590755","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":"Glucagon-Like Peptide-2 Receptor: A Master Integrator of Gut-Brain-Liver Communication in Metabolic and Cognitive Health.","authors":"Yunuo Jiang, Guo Han, Zixu Zhang, Shengru Hu, Mingdao Mu","doi":"10.1002/cph4.70144","DOIUrl":"https://doi.org/10.1002/cph4.70144","url":null,"abstract":"<p><p>Glucagon-like peptide-2 (GLP-2) has historically been defined by its primary role as an intestinal hormone essential for mucosal growth and epithelial barrier integrity. However, a surge of recent research has sparked a paradigm shift, recasting the GLP-2 receptor (GLP-2R) as a master orchestrator of communication between the gut, brain, and liver. This review synthesizes these advances, highlighting the receptor's strategic expression across this tripartite axis and its functional significance in bidirectional signaling pathways. We also detail its distinct quantitative distribution compared to the GLP-1 receptor (GLP-1R). We examine how GLP-2R serves as a molecular hub in these bidirectional signaling networks critical for both metabolic and cognitive health. Through convergent neural and endocrine pathways, GLP-2R modulates appetite, gastrointestinal motility, metabolic homeostasis, and neuroinflammatory processes that underpin cognitive function. These pathways include vagal afferent circuits, sympathetic innervation, and restricted central access via circumventricular organs. Notably, we also address species-specific differences in GLP-2R function and their critical translational significance for human therapeutics. This is particularly relevant regarding appetite regulation and pancreatic expression. We review the latest pharmacological innovations, including long-acting analogs, synergistic dual agonists, and novel delivery systems. These dual agonists specifically leverage the structural and signaling non-overlap between GLP-1R and GLP-2R to unlock the receptor's full therapeutic potential. Finally, we discuss ongoing challenges and highlight specific unanswered mechanistic questions. This positions GLP-2R as both a promising therapeutic target and a fundamental research tool for dissecting the integrated crosstalk between the gut, brain, and liver that governs whole-body physiology and behavior.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70144"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627354","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":"Adventitial Niches, Complement and Inflammation in Pulmonary Vascular Disease: Current Status and Future Directions.","authors":"Hui Zhang, Ram Raj Prasad, Sushil Kumar, Min Li, Dallas Jones, Cheng-Jun Hu, Claudia Mickael, Yen-Rei Yu, Rubin M Tuder, Kurt R Stenmark","doi":"10.1002/cph4.70133","DOIUrl":"10.1002/cph4.70133","url":null,"abstract":"<p><p>There is strong evidence supporting inflammatory and autoimmune processes in the pathogenesis of pulmonary arterial hypertension (PAH), although the initiating and disease-sustaining mechanisms remain unclear. Studies in arthritis, kidney disease, and cancer have demonstrated that dysregulation of the complement system can drive inflammation-mediated tissue injury. We have shown that activation of the complement cascade, particularly the alternative pathway, within the pulmonary vasculature is a key driver of proinflammatory responses in pulmonary hypertension (PH). Single-cell spatial transcriptomic analysis of PAH lungs further revealed complement-rich adventitial fibroblasts, granzyme K (GZMK)⁺ CD8 T cells, and activated macrophages forming proinflammatory niches within the pulmonary artery adventitia in the different pulmonary vascular lesions in PAH. Our recent work highlights the role of both extracellular and intracellular complement activation in fibroblast-mediated pulmonary vascular inflammation. Specifically, activation of the alternative pathway within fibroblasts, through complement factors D (CFD) and B (CFB), promotes production of anaphylatoxins (C3a and C5a), cytokines, and complement-containing extracellular vesicles (EVs). These mediators drive macrophage and T-cell recruitment and activation, contributing to disease progression. Additionally, a fourth pathway of complement activation mediated by CD8⁺ T cell-derived GZMK, which triggers extracellular complement cascades in fibroblasts and macrophages, has recently been identified. These findings support the hypotheses that local complement production by pulmonary artery adventitial fibroblasts, activated intracellularly by CFD and CFB and extracellularly by GZMK⁺, and its secretion in soluble form and within EVs promotes macrophage chemotaxis and activation. These complement-driven proinflammatory niches in PAH pulmonary arteries represent promising therapeutic targets in PH.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70133"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13022472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520267","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":"PVRI-GoDeep-A Global Meta-Registry at the Crossroads of Heart and Lung.","authors":"Meike T Fuenderich, Athiththan Yogeswaran, Patrick Janetzko, Khodr Tello, Werner Seeger, Raphael W Majeed, Jochen Wilhelm","doi":"10.1002/cph4.70118","DOIUrl":"10.1002/cph4.70118","url":null,"abstract":"<p><p>Pulmonary hypertension (PH) is a complex disease characterized by increased pressure in the pulmonary arteries. It encompasses a heterogeneous group of entities that increase right heart afterload and often lead to right heart failure and premature death. Advancing diagnosis, risk stratification, and treatment across the diverse PH spectrum requires large, high-quality, longitudinal datasets that exceed the scope of individual national or regional registries. To address this need, PVRI GoDeep was founded under the umbrella of the Pulmonary Vascular Research Institute (PVRI). This global meta registry harmonizes and integrates anonymized patient-level data from existing PH registries at expert centers worldwide. PVRI GoDeep enables the reuse of locally collected real-world data by mapping heterogeneous datasets to a predefined data dictionary, thorough quality checks, and regular updates. This approach supports phenotyping across all PH groups, enables international comparisons, and allows in-depth analysis of rare subtypes, disease progression, treatment responses, and survival rates. Importantly, GoDeep makes clinically relevant research possible that cannot be conducted at the level of a single center, such as validating risk-stratification tools across PH subgroups, evaluating off-label therapies, and investigating newly recognized entities, such as mild PH. By January 2026, data from more than 45,000 individuals worldwide were integrated into GoDeep, making it one of the largest and most diverse PH registries. Offering a scalable, governed, and disease-independent framework for harmonized real-world evidence generation, PVRI GoDeep is a powerful platform to deepen the understanding of PH and support the development of clinical guidelines for the diagnosis and treatment of PH.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70118"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13013090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147510409","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":"Correction to \"Loss of Y Chromosome Associates with Lung and Cardiac Dysfunction in COPD\".","authors":"","doi":"10.1002/cph4.70151","DOIUrl":"https://doi.org/10.1002/cph4.70151","url":null,"abstract":"","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70151"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764044","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":"Fibroblast-Driven Fibroblast Growth Factor and Fibronectin 1 Signaling Orchestrates Extracellular Matrix Remodeling for Ovine Mammary Lactation Decline.","authors":"Shujuan Liu, Zhanhang Wang, Heran Cao, Jiuzeng Cui, Yonglong He, Yan Li, Xiaopeng An, Lei Zhang, Yuxuan Song","doi":"10.1002/cph4.70150","DOIUrl":"https://doi.org/10.1002/cph4.70150","url":null,"abstract":"<p><p>Lactation decline in sheep is accompanied by extensive mammary gland remodeling, primarily involving extracellular matrix (ECM) reorganization. Here, we integrated single-cell RNA sequencing data from peak (PL) and late lactation (LL) stages to delineate the cellular and molecular mechanisms underlying this process. We identified nine immune cell subtypes and observed marked stage-specific changes in their abundance, highlighting a dynamic immune landscape during lactation regression. Notably, fibroblasts emerged as pivotal stromal regulators, exhibiting high expression of ECM-related genes and mediating collagen restructuring. Ligand-receptor interaction analysis revealed that fibroblasts maintained robust communication with endothelial and immune cells via FGF and FN1 signaling pathways, orchestrating ECM remodeling and structural stabilization. Metabolic profiling further implicated fibroblast-driven valine, leucine, and isoleucine degradation in supporting ECM dynamics. Cross-species comparisons revealed conserved transcriptional programs in fibroblasts and endothelial cells between sheep and humans, underscoring their evolutionarily conserved roles in ECM remodeling and angiogenesis. The study uncovers a fibroblast-driven regulatory network governing postpartum ECM remodeling, providing theoretical insights into the development and reconstruction of mammary tissue, and laying a foundation for investigating lactation dynamics and tissue regression across species.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70150"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716170","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":"Look Who Is Talking: Extracellular Vesicles as Mediators of Intercellular and Interorgan Communication.","authors":"Michela Saviana, Giulia Romano, Daniel Del Valle-Morales, Mario Acunzo, Patrick Nana-Sinkam","doi":"10.1002/cph4.70128","DOIUrl":"10.1002/cph4.70128","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are produced by every organ, serving as vehicles for communication. By circulating throughout the body and targeting both neighboring and distant cells and organs, they can drive downstream signaling. EVs play a role as effectors of cell-to-cell communication in the tissue microenvironment and have demonstrated their importance in driving downstream biological processes, maintenance of homeostasis and response to stimuli. New methodologies supporting the study of EV-mediated long-distance communication have revealed a whole new unexplored function in maintaining homeostasis of the organism and serving as indicators of pathological conditions. In this review, we provide the most recent update on the role of EVs as mediators of intercellular and interorgan communication.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 2","pages":"e70128"},"PeriodicalIF":5.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13055575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627393","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}