Collateral damage: necroptosis in the development of lung injury

Abstract

Cell death is increasingly recognized as a driving factor in the development of acute lung injury. Necroptosis, an immunogenic regulated cell death program important in innate immunity, has been implicated in the development of lung injury in a diverse range of conditions. Characterized by lytic cell death and consequent extracellular release of endogenous inflammatory mediators, necroptosis can be both beneficial and deleterious to the host, depending on the context. Here, we review recent investigations linking necroptosis and the development of experimental lung injury. We assess the consequences of necroptosis during bacterial pneumonia, viral infection, sepsis, and sterile injury, highlighting increasing evidence from in vitro studies, animal models, and clinical studies that implicates necroptosis in the pathogenesis of ARDS. Lastly, we highlight current challenges in translating laboratory findings to the bedside.

The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach

“…Pyroptosis and necroptosis of alveolar epithelial and endothelial cells are major elements in development and progression of ARDS in part by releasing high mobility group box 1 (HMBG1) and other inflammatory damage-associated molecular patterns (DAMPs) [ [89] , [90] , [91] ]. Hence, the pyroptotic death of type 2 alveolar cells following SARS-Cov2 infection may also be of pathophysiological significance in the development of COVID-19 and a major source of inflammation [ 85 , 86 ].…”

“…As previously discussed, pyroptosis and necroptosis of alveolar epithelial and endothelial cells are major elements in the development and progression of ARDS [ [89] , [90] , [91] ]. There is also evidence to suggest that the pyroptotic death of neutrophils makes an independent contribution to the exacerbation of inflammation in more advanced stages of the condition [ 203 ].…”

“…There is now accumulating evidence to suggest that the escalating increases in levels of IL-6, TNF-alpha, nitric oxide (NO) and ROS secreted by macrophages [ [92] , [93] , [94] ] also make a significant contributions to mortality by stimulating widespread cellular RIPK mediated necroptosis [ 89 , 94 ]. This form of cell death is associated with massive increases in levels of HGMB1, mtDNA, PICs, chemokines and ROS with ever amplifying levels of tissue damage, described as necroinflammation [ 267 , 268 ], leading to irreversible lung failure [ 269 ].…”

“…This form of cell death is associated with massive increases in levels of HGMB1, mtDNA, PICs, chemokines and ROS with ever amplifying levels of tissue damage, described as necroinflammation [ 267 , 268 ], leading to irreversible lung failure [ 269 ]. Necroptosis is predictive of non-resolving ARDS and mortality in patients on mechanical ventilation [ 89 , 94 ]. The pathological consequences of programmed cell death are difficult to overstate as studies have reported a causative association between the advent of widespread RIP Kinase-dependent necroptosis and the development of multiple organ failure and death in systemic inflammatory response syndrome and sepsis [ 270 ].…”

Serum levels of receptor-interacting protein kinase-3 in patients with COVID-19

“…Shashaty et al demonstrated that among patients with sepsis or trauma, the change in plasma RIPK-3 levels 48 h after admission was independently associated with ARDS [3]. Because RIPK-3 mediates not only necroptosis but also other inflammatory pathways [2], the elevation of RIPK-3 does not directly indicate the execution of necroptosis. To confirm the role of RIPK-3 in COVID-19-ARDS patients, further studies are needed including a larger number of participants and histological evaluation of lung tissues, especially since RIPK-3-mediated necroptosis could be a potential therapeutic target for COVID-19-related ARDS.…”