{"id":1008,"date":"2025-06-11T06:00:37","date_gmt":"2025-06-11T06:00:37","guid":{"rendered":"https:\/\/perfusfind.com\/ic\/?p=1008"},"modified":"2025-06-10T18:44:05","modified_gmt":"2025-06-10T18:44:05","slug":"macrophage-pyroptosis-and-its-crucial-role-in-ali-ards","status":"publish","type":"post","link":"https:\/\/perfusfind.com\/ic\/index.php\/2025\/06\/11\/macrophage-pyroptosis-and-its-crucial-role-in-ali-ards\/","title":{"rendered":"Macrophage pyroptosis and its crucial role in ALI\/ARDS"},"content":{"rendered":"
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Summary:<\/strong> “Macrophage Pyroptosis and its Crucial Role in ALI\/ARDS”<\/strong><\/p>\n<\/blockquote>\n

Abstract Summary:<\/strong> This comprehensive review explores macrophage pyroptosis, a specific form of programmed cell death, and its pivotal role in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Highlighting complex molecular pathways and inflammasome activation mechanisms, the authors detail the relationship between macrophage pyroptosis and exacerbated lung inflammation and damage, proposing various potential therapeutic interventions that target macrophage pyroptosis to improve clinical outcomes in ALI\/ARDS.<\/p>\n

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Pathological features of ALI\/ARDS. The pathologic features of ALI\/ARDS include diffuse necrosis of alveolar capillary endothelial cells and epithelial cells, increased permeability of the pulmonary capillary endothelial and alveolar epithelial barriers, accumulation of protein-rich edema fluid, extensive pulmonary hemorrhage, and thrombosis in the alveolar hyaloid membrane and capillaries.<\/figcaption><\/figure>\n

Key Points:<\/strong><\/p>\n

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    Overview of ALI\/ARDS:<\/strong> ALI\/ARDS is characterized by severe respiratory distress, hypoxemia, and diffuse lung injury, resulting in mortality rates between 35-46%. Its development involves excessive immune responses triggered by pulmonary and extrapulmonary factors.<\/p>\n<\/li>\n

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    Definition and Mechanisms of Pyroptosis:<\/strong> Pyroptosis, distinct from apoptosis, is mediated by gasdermin proteins, resulting in membrane pore formation, cell swelling, and inflammatory cytokine release, crucially influencing immune responses and tissue damage in lung injury.<\/p>\n<\/li>\n

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    Role of Inflammasomes in Pyroptosis:<\/strong> Inflammasome activation (canonical via caspase-1; non-canonical via caspase-4\/5\/11) triggers pyroptosis through the cleavage of gasdermin-D, releasing pro-inflammatory cytokines IL-1\u03b2 and IL-18, intensifying lung injury.<\/p>\n<\/li>\n

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    Macrophage Pyroptosis in Lung Injury:<\/strong> Macrophages, critical pulmonary immune cells, significantly contribute to ALI\/ARDS pathogenesis through excessive activation and pyroptosis, worsening inflammation, cytokine storms, and tissue destruction.<\/p>\n<\/li>\n

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    Impact of Mitochondrial Dysfunction on Pyroptosis:<\/strong> Impaired mitophagy and mitochondrial dysfunction enhance macrophage pyroptosis via elevated reactive oxygen species (ROS) and inflammasome activation, exacerbating ALI\/ARDS severity.<\/p>\n<\/li>\n

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    Exosomes in Macrophage Pyroptosis Regulation:<\/strong> Exosomes derived from polymorphonuclear neutrophils (PMNs) can aggravate pyroptosis by transferring inflammatory microRNAs; conversely, exosomes from mesenchymal stem cells (MSCs) inhibit pyroptosis, highlighting their therapeutic potential.<\/p>\n<\/li>\n

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    Neutrophil Extracellular Traps (NETs):<\/strong> NETs exacerbate macrophage pyroptosis and ALI\/ARDS via AIM2 inflammasome activation. Targeting NET formation may thus mitigate inflammation and improve patient outcomes.<\/p>\n<\/li>\n

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    Post-translational Modifications (PTMs):<\/strong> Various PTMs, including ubiquitination and phosphorylation, critically regulate inflammasome and gasdermin protein activation, suggesting therapeutic targets for inhibiting pyroptosis in ALI\/ARDS.<\/p>\n<\/li>\n

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    Therapeutic Approaches Targeting Pyroptosis:<\/strong> Emerging therapeutic agents such as melatonin, mesenchymal stem cell-derived exosomes, alpha-linolenic acid, and specific drugs (e.g., sacubitril\/valsartan) demonstrate efficacy in reducing macrophage pyroptosis and attenuating ALI\/ARDS severity.<\/p>\n<\/li>\n

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    Future Challenges and Research Directions:<\/strong> Current understanding of macrophage pyroptosis is incomplete. Clinical translation faces significant challenges due to limited preclinical evidence, complexity of delivery systems, potential off-target effects, and the need for robust clinical trials.<\/p>\n<\/li>\n<\/ol>\n

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    Molecular mechanism of pyroptosis. In the canonical inflammasome pathway, the majority of inflammasome complex is assembled from intracellular sensor protein, adapter proteins ASC and effector protein caspase. When PAMPs or DAMPs such as toxins, bacteria, viruses and dsDNA intrude, the NLRP1 and NAIP\/NLRC4 can directly convert pro-caspase-1 into active caspase-1 because both of them have the CARD to connect with pro-caspase-1, while the AIM2, NLRP3, PYRIN and NLRP6 have to bind with ASC firstly before activating the pro-caspase-1 due to the lack of CARD. Active caspase-1 cleaves the GSDMD to causing damage to cell membrane and formation of perforations meanwhile cleaves pro-IL-1\u03b2 and pro-IL-18 and results in the maturation of IL-1\u03b2 and IL-18 that are subsequently released from the N-GSDMD pores. In the non-canonical inflammasome pathway, LPS directly binds to pro-caspase-4\/5\/11, resulting in activation of caspase-4\/5\/11, which cleaves GSDMD to trigger pyroptosis. In the granzyme-A\/B-dependent pyroptosis pathway, GzmA and GzmB from NK cells and CD8\u2009+\u2009T cells enter cancer cells via perforin and recognise GSDMB and GSDME, respectively, to induce pyroptosis. In addition, chemotherapeutic drugs and Y. pestis trigger pyroptosis through the caspase-3\/GSDME or caspase-8\/GSDMD cascades.<\/figcaption><\/figure>\n

    Conclusion:<\/strong> Macrophage pyroptosis significantly influences ALI\/ARDS pathology, contributing to severe pulmonary inflammation and tissue damage. Targeting macrophage pyroptosis through various pharmacological and therapeutic strategies represents a promising avenue for improving clinical outcomes, though substantial challenges remain in clinical translation and practical implementation.<\/p>\n

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    The distribution of macrophage populations in the lung. Macrophages in the lungs are composed of Alveolar macrophages (AMs) and interstitial macrophages (IMs). AMs are located in the alveoli, and IMs reside in the parenchyma between the microvascular endothelium and alveolar epithelium. When there is pulmonary inflammation and injury, circulating monocytes in capillaries are subsequently recruited to the lungs and converted into AM-like cells.<\/figcaption><\/figure>\n
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    Macrophage pyroptosis and its crucial role in ALI\/ARDS<\/figcaption><\/figure>\n
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    Watch the following video on “Dr. Lieberman: SARS-CoV \u2013 Monocyte and Macrophage Infection, Inflammasome Activation and Pyroptosis” by Human Immunome Project<\/strong><\/p>\n