Pyroptosis in acute respiratory distress syndrome and pulmonary fibrosis.

ARDS (acute respiratory distress syndrome) and PF (pulmonary fibrosis) are severe pulmonary conditions with significant morbidity and mortality. This review focuses on the pyroptosis, a lytic, pro-inflammatory form of programmed cell death, as a central mechanism linking these two pathologies. We address how inflammasome activation stimulates the pyroptosis initiation and subsequently releases a cascade of inflammatory cytokines that drive the acute lung injury of ARDS. Subsequently, we elucidate how this sustained pyroptotic inflammation, combined with shifts in macrophage polarization, creates a pro-fibrotic microenvironment that promotes fibroblast activation and extracellular matrix deposition, thereby mechanistically driving the transition from ARDS to PF. The pathological landscape, from the early stage of ARDS to PF, is further shaped by a dynamic interaction between pyroptosis, necroptosis, and ferroptosis, with the temporal dominance of each pathway influencing the progression from acute inflammation to chronic fibrosis. Particularly, the clinical relevance of these mechanisms is also addressed in COVID-19-induced ARDS. Therefore, targeting key regulators of this axis, such as the NLRP3 inflammasome and the effector protein Gasdermin D, presents a promising therapeutic strategy to alleviate inflammatory responses upon tissue damage and halt fibrotic progression, offering new hope for these severe lung diseases.