Pharmacological Reviews最新文献

{"title":"Vein graft failure: Pathophysiology, detection, prevention and emerging therapeutic strategies.","authors":"Simon D Brown, Sandra Sanchez-Esteban, Laura Clark, Katarina Miteva, Georgios Krilis, Rachael O Forsythe, Stuart A Nicklin, Samantha Carmichael, Colin Berry, Nawwar Al-Attar, David E Newby, Andrew H Baker","doi":"10.1016/j.pharmr.2026.100139","DOIUrl":"10.1016/j.pharmr.2026.100139","url":null,"abstract":"<p><p>Coronary and peripheral artery bypass graft surgery remain cornerstones of cardiac and vascular surgery, respectively. They utilize the saphenous vein as the preferred conduit, although it suffers from poor midterm and long-term outcomes, with the grafted vein often becoming occluded. Current therapeutic approaches aim to manage complications rather than prevent graft failure directly, and despite progress, failure rates have remained unchanged in decades, meaning there remains an unmet clinical need for novel therapeutic approaches. As access to the grafted tissue is available at the time of surgery, coronary and peripheral artery bypass graft are particularly suited to perioperative therapeutic manipulation and intervention that can be delivered locally and directly to the tissue immediately before grafting. Ongoing research attempts to uncover novel genes driving bypass graft failure that can be targeted for such therapies. In addition to protein-coding genes, multiple examples of noncoding genes driving graft failure are now described, including microRNAs and long noncoding RNAs with cell type-specific roles. The increasing wealth of single cell, single nuclei and spatial transcriptomic data related to cardiovascular pathologies are revealing novel target loci that could facilitate greater specificity for target manipulation in specific pathogenic cell types. In parallel, extensive research continues to develop advanced imaging techniques that can be used to monitor the patency of grafts over time, and guide the effective design of advanced therapies. Here, we discuss the progress in these areas and highlight how harmony among these will accelerate therapeutic progress toward vein graft disease. SIGNIFICANCE STATEMENT: Coronary or peripheral artery bypass surgery using saphenous vein grafts are among the most commonly performed cardiovascular surgeries for advanced vascular occlusions. However, both suffer from poor long-term graft patency. The continued development of next-generation multiomics technologies and advanced therapies are illuminating new therapeutic targets that offer hope toward novel precision medicines for peripheral and coronary artery bypass graft failure.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100139"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148164058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aryl hydrocarbon receptor pharmacology-mechanisms, ligands, and therapeutic potential.","authors":"Raitis Bobrovs, Ninni Elise Olafsen, Samaneh Shabani Åhrling, Jason Matthews","doi":"10.1016/j.pharmr.2026.100146","DOIUrl":"10.1016/j.pharmr.2026.100146","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that has emerged as a key modulator of several physiological and pathological processes. Historically, AHR has been studied for its role as a mediator of the toxic responses of environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Because of this, its potential as a therapeutic target was overlooked. AHR is now regarded as a multifunctional regulator of inflammation, immunity, barrier tissue integrity, metabolism, and cancer biology. AHR signaling is modulated by an array of structurally diverse endogenous, microbial, dietary, pharmaceutical, and xenobiotic ligands. AHR exhibits extensive crosstalk with many signaling pathways, which contributes to highly context-specific biological outcomes. Recent advances and enhanced interest in AHR pharmacology have accelerated the development of therapeutically relevant AHR ligands, including the clinically approved AHR agonist, tapinarof, for the treatment of psoriasis and atopic dermatitis, as well as emerging AHR antagonist strategies in cancer immunotherapy. Structural efforts have succeeded in providing valuable insight into ligand-AHR interactions that will further contribute to improved and rational design of AHR ligands. However, significant challenges remain, including AHR ligand promiscuity, complex negative feedback regulation, extensive signaling crosstalk, and long-term safety concerns. Here, we review the molecular mechanisms of AHR activation, its physiological and pathological functions, and the current advances of its therapeutic targeting. SIGNIFICANCE STATEMENT: The aryl hydrocarbon receptor (AHR) has emerged from its origins in toxicology to become a promising clinically relevant target for the treatment of dermatological, gastroenterological, and autoimmune diseases as well as cancer. This review summarizes the current knowledge of AHR pharmacology, including molecular signaling, endogenous and exogenous ligands, physiological and pathological functions, present and emerging therapeutic targeting strategies, as well as challenges that remain for translation into safe clinical therapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100146"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reharnessing the therapeutic potential of gallium-based compounds in oncology: From the laboratory to the clinic.","authors":"Christopher R Chitambar, Casey J Zoss, Mona M Al-Gizawiy, Kathleen M Schmainda, Jennifer M Connelly","doi":"10.1016/j.pharmr.2026.100138","DOIUrl":"10.1016/j.pharmr.2026.100138","url":null,"abstract":"<p><p>Despite advances in the treatment of certain malignancies, it is anticipated that there will be 626,140 cancer deaths in the United States in 2026. Thus, there remains a great need to develop new antineoplastic drugs with unique mechanisms of action distinct from those of existing drugs. Also relevant is revisiting agents that showed promise in early research. Some of these agents struggled to advance for reasons including an incomplete understanding of their molecular targets and insufficient commitment to pursuing their development. Gallium compounds initially gained attention as radiogallium ⁶⁷Ga complexes for tumor imaging in cancer patients, but were later found in clinical trials of nonradioactive gallium nitrate to have antineoplastic activity against lymphoma and urothelial malignancies. Coincident with this, tris(8-quinolinolato)gallium(III) has been shown to be active against solid tumors and has now re-emerged in clinical trials as oral AP-002. Subsequent investigations showed that gallium exerts its antineoplastic activity by disrupting iron-dependent processes essential to cancer development and growth. Recent preclinical studies of oral gallium maltolate demonstrated its activity against glioblastoma, an aggressive brain tumor, leading to a Food and Drug Administration-approved phase 1 clinical trial for patients with relapsed glioblastoma. This review will focus on the evolution of gallium compounds in malignancy; advances in our knowledge of their mechanisms of action and tumor resistance; their interactions with cellular iron homeostasis and other targets; the past and present preclinical and clinical experience with gallium compounds; and the development of promising gallium-based agents on the horizon. SIGNIFICANCE STATEMENT: Gallium compounds showed anticancer activity in early clinical studies; however, an incomplete understanding of their mechanisms of action and resistance hindered the selection of patients most likely to benefit from treatment. Herein, we review the development of gallium compounds from early preclinical research to clinical trials for cancer. Recent insights into gallium's molecular targets have advanced the translation of gallium from the laboratory to a clinical trial of oral gallium maltolate in glioblastoma. Newer gallium compounds are being developed; their advancement is eagerly anticipated.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100138"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mast cell proteases and their significance in physiology, pathology, and therapeutic approaches.","authors":"Afshin Derakhshani, Leela Mahajan, Kyle Lesack, Navid Saranjam, Khashayarsha Khazaie, Gunnar Pejler, Roman Krawetz, Laura E Edgington-Mitchell, Henry R Maun, Antoine Dufour","doi":"10.1016/j.pharmr.2026.100144","DOIUrl":"10.1016/j.pharmr.2026.100144","url":null,"abstract":"<p><p>Mast cells (MCs) are versatile, multifunctional immune cells with broad roles in physiological homeostasis and pathogenic processes. MCs are found in most tissues, including skin, lungs, intestines, and peritoneum, and they vary in numbers, types, and biological functions. MCs are implicated in host defense against various pathogens, including bacteria, viruses, and fungi. Additionally, MCs are crucial in protecting against toxins, including those present in venoms from multiple species, such as honeybees, snakes, scorpions, and lizards. Although MCs play an essential role in host defense, they are mostly known for their detrimental actions in allergic reactions, such as asthma, food allergy, anaphylaxis, mastocytosis, and various inflammatory skin conditions. Under such conditions, MCs are activated (via IgE-mediated or other mechanisms) and release a range of potent proinflammatory mediators, including tumor necrosis factor α. In addition to cytokines, they are major producers of histamine and various proteases, including chymase, tryptase, and carboxypeptidase A3. As a result, these mediators contribute to the pathological manifestations associated with inflammatory conditions and other disorders. This review focuses mainly on the biological role of MCs and their proteases, with a focus on chymase and tryptase, as well as their inhibitors as candidate therapies for MC-driven diseases. SIGNIFICANCE STATEMENT: Mast cells (MCs) and their proteases are central regulators of tissue homeostasis, barrier defense, and inflammation across multiple organs, but are also associated with numerous diseases. Ongoing research has shown that the function of MCs is highly dependent on their tissue location, where the local tissue environment shapes their phenotype, protease expression, and, consequently, their biological functions. However, further investigation is required to more precisely understand the physiological conditions governing the transition of MCs from maintaining tissue homeostasis to acquiring pathogenic functions, particularly with respect to their protease-dependent activities. By profiling MC heterogeneity using multiomics approaches to map protease-driven signaling networks, it will be possible to gain deeper insight into their functional roles and establish a conceptual framework to guide the development of next-generation, mechanism-based therapeutics that selectively modulate MC activity in human diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100144"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Friend or foe? Glial-vascular interactions in health and neurodegenerative disease.","authors":"Conor McQuaid, Michael Sewell, Axel Montagne","doi":"10.1016/j.pharmr.2026.100143","DOIUrl":"10.1016/j.pharmr.2026.100143","url":null,"abstract":"<p><p>Dysfunction of glial and vascular cells is increasingly recognized as a central feature of neurodegenerative diseases. Growing evidence points to disruptions in glial-vascular interactions, which are critical for maintaining the functions of the neurogliovascular unit throughout the lifespan, as key contributors to disease initiation and progression. However, the mechanisms governing this complex intercellular crosstalk and its potential role in disease pathogenesis remain incompletely understood. In this review, we summarize the current understanding of glial-vascular communication across health and disease, with a particular focus on Alzheimer disease, stroke, cerebral small vessel disease, Parkinson disease, Huntington disease, and multiple sclerosis. We highlight emerging cellular and molecular interactions of interest, outline major gaps in our understanding, and discuss innovative tools, including transcriptomics, which are reshaping the study of neurogliovascular dynamics. A central unresolved question is whether glial and/or vascular dysfunction represents the primary initiating event across neurodegenerative diseases, or whether these processes emerge in parallel through shared upstream drivers. Unraveling these interactions may ultimately reveal novel therapeutic opportunities for a broad range of neurodegenerative conditions. SIGNIFICANCE STATEMENT: Neurogliovascular unit interactions are fundamental to brain homeostasis, yet the molecular basis of this crosstalk and its disruption in neurodegeneration remains poorly understood. This review provides the first comprehensive synthesis of molecular mechanisms governing the Neurogliovascular unit interface across physiological and pathological conditions, integrating evidence from related disorders. By consolidating key signaling pathways, disease-associated alterations, and emerging experimental approaches, this review offers a unifying framework to guide biomarker development and therapeutic targeting.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 4","pages":"100143"},"PeriodicalIF":20.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting of kinases to treat neurodegenerative diseases.","authors":"Tara Shomali, Jean-François Trempe","doi":"10.1016/j.pharmr.2026.100128","DOIUrl":"10.1016/j.pharmr.2026.100128","url":null,"abstract":"<p><p>Neurodegenerative diseases, including Alzheimer, Parkinson, and multiple sclerosis, represent a growing global health crisis with limited therapeutic options that address disease progression. Protein kinases, which are crucial regulators of diverse cellular processes such as endolysosomal trafficking, neuroinflammation, and mitochondrial homeostasis, are frequently dysregulated in these conditions, making them attractive drug targets. This review explores the therapeutic potential of targeting key kinases implicated in neurodegeneration, specifically p38 MAPK, BTK, c-Abl/ABL1, CDK5, GSK3, JNK, LRRK2, and PINK1. We delve into their specific roles in disease pathophysiology, current therapeutic strategies, and the structural insights guiding our understanding of these kinases and the development of more selective inhibitors. Although significant challenges remain, particularly regarding selectivity and drug delivery to the brain, the advancements in our understanding of kinase biology and novel therapeutic modalities offer substantial promise for developing disease-modifying treatments. This review highlights the urgent need for continued research to identify new targets and translate these scientific breakthroughs into effective therapies for patients. SIGNIFICANCE STATEMENT: This review outlines the roles of protein kinases in neurodegenerative diseases and highlights emerging strategies for their therapeutic modulation. By integrating current knowledge of kinase signaling, drug development, and pharmacokinetics, this work provides a timely and practical framework to guide the development of disease-modifying treatments in an area of pressing clinical need.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100128"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adhesion G protein-coupled receptors.","authors":"Tobias Langenhan, Garret R Anderson, Demet Araç, Gabriela Aust, Monserrat Avila-Zozaya, Sofie Morsing Bagger, Patrick Barth, Sandra Berndt, Stephen C Blacklow, Beatriz Blanco-Redondo, Antony A Boucard, James P Bridges, Lara-Sophie Brodmerkel, Kathleen M Caron, Yin Kwan Chung, Andrew N Dates, Virginea de Araujo Farias, Daniel Del Toro, Joseph G Duman, Felix B Engel, David M Favara, Caroline J Formstone, Chaoyu Fu, Alain Garcia De Las Bayonas, Anastasia Georgiadi, David E Gloriam, Randy A Hall, Jörg Hamann, Peter W Hildebrand, Cheng-Chih Hsiao, Bill X Huang, Jonathan A Javitch, Hee-Yong Kim, Robert J Kittel, Gunnar Kleinau, Richard Leduc, Ines Liebscher, Hsi-Hsien Lin, Joshua Linnert, Marie-Gabrielle Ludwig, David C Martinelli, Signe Mathiasen, Daniel Matúš, Mariam Melkumyan, Ana L Moreno-Salinas, Jan Mulder, Michael A Nash, Kasturi Pal, Daniel T Pederick, Nicole A Perry-Hauser, Xianhua Piao, Yu-Qi Ping, Dimitris G Placantonakis, Fabian Pohl, Simone Prömel, Mette M Rosenkilde, Laurent Sabbagh, Richard C Sando, Patrick Scheerer, Torsten Schöneberg, Elena Seiradake, Mareike Selcho, Florian Seufert, Abhishek K Singh, Georgios Skiniotis, Katja Spiess, Norbert Sträter, David Strutt, Thomas C Südhof, Jinpeng Sun, Gregory G Tall, Doreen Thor, Douglas G Tilley, Kimberley F Tolias, Mario Vallon, Erwin G Van Meir, Benoit Vanhollebeke, Giselle R Wiggin, Uwe Wolfrum, Jie Yan, Nathan A Zaidman, Yimin Zou, Nicole Scholz","doi":"10.1016/j.pharmr.2026.100116","DOIUrl":"10.1016/j.pharmr.2026.100116","url":null,"abstract":"<p><p>Adhesion G protein-coupled receptors (aGPCRs) constitute a structurally and functionally distinct group within the superfamily of GPCRs. In 2015, the International Union of Pharmacology invited the Adhesion GPCR Consortium to publish a comprehensive review about aGPCRs and establish a unified nomenclature. Since then, substantial progress has been made in delineating the biological roles, molecular architecture, biochemical properties, expression profiles, ligand repertoire, and activation and signaling strategies of aGPCRs. Commensurate with these advances, their relevance to human pathophysiology has become increasingly apparent. In a coordinated effort, the Adhesion GPCR Consortium has reviewed recent progress in this field and provides a comprehensive assessment of the current understanding of aGPCR biology, including a focus on human and mammalian aGPCRs, their evolutionary origins, methodological approaches, and model systems for their investigation, as well as emerging approaches for their therapeutic targeting. SIGNIFICANCE STATEMENT: Adhesion G protein-coupled receptors are versatile cell-surface proteins that integrate structural, biochemical, and physiological functions, with major roles in health and disease. This review summarizes current knowledge of their molecular features, functions in diverse model systems, and emerging opportunities for therapeutic targeting, providing a comprehensive resource that connects basic biology with translational applications across multiple scientific disciplines.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100116"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147531629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging mechanistic trends and clinical efficacy for methotrexate: Applications to inflammatory bowel disease.","authors":"Jeehyun Karen You, Theresa T Pizarro, Tommaso L Parigi","doi":"10.1016/j.pharmr.2026.100132","DOIUrl":"10.1016/j.pharmr.2026.100132","url":null,"abstract":"<p><p>Methotrexate (MTX) was among the first steroid-sparing agents introduced for the treatment of inflammatory bowel disease (IBD). Its efficacy is well established for Crohn's disease, though studies of its use in ulcerative colitis have largely reported negative results, with only some, although inconsistent, findings suggesting limited benefit. In this review, we provide a comprehensive and up-to-date evaluation of MTX's use in IBD, including its key mechanisms of action(s), therapeutic value, as well as emerging targets that underscore the complexity of this drug and the biological landscape it alters. Despite its longstanding use, the full spectrum of MTX's effects contributing to its efficacy in IBD remains incompletely understood. Although multiple pathways have been implicated, the relative importance of each remains nebulous, and additional, unidentified functions may play a role, particularly in contexts not pertaining to immunomodulation. We highlight recent findings that poise MTX as an unexpected but promising agent for mucosal healing. We also provide a detailed evaluation of clinical studies, encompassing randomized controlled trials and observational data, highlighting MTX's effectiveness, differences in route of administration, safety profile, and limitations as they pertain to the management of IBD. As therapeutic targets for IBD evolve, we discuss MTX's future positioning by exploring clinical perspectives regarding its utility and examine the latest evidence that indicates there may be novel, previously unexplored, therapeutic potential. By bridging mechanistic insights with clinical evidence, this review underscores MTX's enduring, albeit niche, position in IBD therapy and highlights key areas for future investigation to optimize its use. SIGNIFICANCE STATEMENT: Methotrexate remains a valuable, though underutilized, therapeutic option for the management of inflammatory bowel disease. This review provides a comprehensive overview of methotrexate's pharmacology, integrating emerging mechanistic insights and clinical data to reframe its role beyond immunomodulation, particularly at the gastrointestinal mucosal interface, thereby identifying novel avenues for future research that may expand its clinical utility in inflammatory bowel disease.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100132"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epithelial cells in chronic obstructive pulmonary disease exacerbations: Targets for lung repair.","authors":"Wei Ji, Hayriye Akel Bilgic, Maarten van den Berge, Huib A M Kerstjens, Gert Folkerts, Reinoud Gosens, Saskia Braber","doi":"10.1016/j.pharmr.2026.100131","DOIUrl":"10.1016/j.pharmr.2026.100131","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic respiratory symptoms and persistent, often progressive, loss of lung function. Patients, particularly those with severe disease, frequently experience exacerbations triggered by viral and bacterial infections. Exacerbations are closely linked to the rapid decline in lung function, accounting for more than 50% of the accelerated loss over the lifetime of a patient with COPD. Airway epithelial cells play a central role in the development of COPD exacerbations. As the first line of defense, these cells form tight intercellular junctions, creating a protective barrier against pathogens and producing mucus and antimicrobial peptides to eliminate bacteria and viruses. Upon pathogen recognition via pattern recognition receptors, epithelial cells initiate inflammatory responses by releasing cytokines and chemokines that recruit immune cells. This inflammation can become dysregulated in COPD, contributing to tissue damage and exacerbation severity. Furthermore, airway epithelial cells are particularly important in promoting lung repair and restoring homeostasis. They modulate inflammation resolution, promote extracellular matrix remodeling, and support lung regeneration. In COPD, chronic inflammation and repeated exacerbations impair epithelial function, disrupt repair mechanisms, and hinder lung regeneration, contributing to irreversible damage. This review highlights the crucial role of airway epithelial cells in COPD exacerbations, focusing on their regulatory functions in maintaining barrier integrity, managing inflammation and promoting epithelial lung repair. Moreover, current and future therapeutic strategies aimed at enhancing epithelial barrier function, controlling airway inflammation, and supporting lung recovery and regeneration are discussed, highlighting key directions for future investigation. SIGNIFICANCE STATEMENT: Chronic obstructive pulmonary disease exacerbations represent a pharmacologically actionable period characterized by epithelial barrier disruption, dysregulated inflammation, and impaired repair. This review positions airway epithelial cells as central orchestrators of these processes, regulating host defense, immune interactions, and regenerative responses. By targeting epithelial dysfunction during exacerbations, this review highlights the potential therapies that go beyond symptom relief and support lung repair and modify disease progression.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100131"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reimagining pharmacology education.","authors":"Clare Guilding, Roisin Kelly-Laubscher, Margaret Cunningham, Tinne Dilles, David Kennedy, David J Brinkman, Ali H Eid, Kelly M Quesnelle, Ferdi Engels, Simon Maxwell, Arthur Christopoulos, Paul J White","doi":"10.1016/j.pharmr.2026.100126","DOIUrl":"10.1016/j.pharmr.2026.100126","url":null,"abstract":"<p><p>We are arguably experiencing the greatest disruption to higher education in modern history. High-quality education research has demonstrated that active learning and other innovations are significantly more effective than traditional methods. The recent pandemic forced educators to adapt in previously unimaginable ways. Generative artificial intelligence now presents great challenges and opportunities for our approaches to teaching, support of learning and assessment, such as streamlining personalized feedback while raising concerns about academic integrity. This article provides a research informed, expert commentary to support new pharmacology educators in navigating this complex environment. The article is neither a systematic review by design and methodology, nor is it offering comprehensive coverage of the pertinent literature (an insurmountable task, given the breadth of the topic). We highlight how educators in basic and clinical pharmacology are transforming their teaching and curricula to enhance student success in current and future settings. Global initiatives, such as those sponsored by the International Union of Basic and Clinical Pharmacology, including the Pharmacology Education Project and Core Concepts-based curricula, are offering opportunities to enhance pharmacology education by standardizing key concepts, providing open-access learning resources, and fostering international collaboration. These efforts are intended to support alignment of curricula, improve student engagement through interactive materials, facilitating a global exchange of best practices, and supporting educators in adopting innovative teaching methodologies. These initiatives require contributions from pharmacology experts across multiple countries, languages, and cultures. Consequently, this article serves as a call to action to advance innovation and inclusivity in pharmacology education. SIGNIFICANCE STATEMENT: Recent disruptions in higher education have forced educators to adapt in ways that would have previously been unthinkable. The article provides an evidence-based, expert commentary for new pharmacology educators that will assist them to thrive in this complex environment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 3","pages":"100126"},"PeriodicalIF":20.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13197921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147778013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}