NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns

Surolia, Ranu; Li, Fu Jun; Wang, Zheng; Kashyap, Mahendra; Srivastavá, R. C.; Traylor, Amie M.; Singh, Pooja; Dsouza, K.G.; Kim, Hyung Min; Pittet, Jean–François; Żmijewski, Jaroslaw W.; Agarwal, Anupam; Athar, Mohammad; Ahmad, Aftab; Antony, Veena B.

doi:10.1172/jci.insight.147564

Cited by 30 publications

(23 citation statements)

References 72 publications

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“…Pericarditis, kidney damage, neurologic, and psychiatric manifestations are among the clinical manifestations of a subset of the COVID-19 patients (8,11,12,36). While NETs have been detected in lung samples in COVID-19 and patients with ARDS secondary to other causes (58)(59)(60)(61)(62)(63)(64), it remains to be determined whether NETs in extrapulmonary tissues during and after COVID-19 in adults and pediatric patients are associated with prognosis, disease manifestations, or development of long COVID. Here, we were able to detect citH4 positive structures in skin from pediatric patients affected by CLL and in autopsy tissues from adult subjects who died from severe COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

Carmona-Rivera¹,

Yu²,

Dobbs³

et al. 2022

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

Carmona-Rivera¹,

Yu²,

Dobbs³

et al. 2022

JCI Insight

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“…However, due to the large microvascular bed and the long transit time, the lung represents a preferred site for the accumulation of activated neutrophils after trauma (154). NET release has been demonstrated in several experimental models of trauma (63,(155)(156)(157), and elevated levels of circulating NET markers have been associated with the worst clinical outcomes in subjects developing trauma-related ARDS (50). Interestingly, ARDS resulting from trauma seems to be overall associated with better clinical outcomes when compared to other forms of ARDS, suggesting the presence of peculiar immunological features (158-161).…”

Section: Traumamentioning

confidence: 99%

The role of neutrophil extracellular traps in acute lung injury

et al. 2022

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Acute lung injury (ALI) is a heterogeneous inflammatory condition associated with high morbidity and mortality. Neutrophils play a key role in the development of different forms of ALI, and the release of neutrophil extracellular traps (NETs) is emerging as a common pathogenic mechanism. NETs are essential in controlling pathogens, and their defective release or increased degradation leads to a higher risk of infection. However, NETs also contain several pro-inflammatory and cytotoxic molecules than can exacerbate thromboinflammation and lung tissue injury. To reduce NET-mediated lung damage and inflammation, DNase is frequently used in preclinical models of ALI due to its capability of digesting NET DNA scaffold. Moreover, recent advances in neutrophil biology led to the development of selective NET inhibitors, which also appear to reduce ALI in experimental models. Here we provide an overview of the role of NETs in different forms of ALI discussing existing gaps in our knowledge and novel therapeutic approaches to modulate their impact on lung injury.

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“…Increasing evidence implicates release of neutrophil extracellular traps (NETs), NETosis, may drive lung injury, specifically ER stress in epithelial cells (9,26,31,32). Our study shows that not only are ER stress markers increased in the pristane model of IFN-inducible SLE, but that inhibition of NETosis using LysMCrePad4 fl/fl mice in this model prevented pristaneinduced ER stress and, more importantly, lung inflammation.…”

Section: Discussionmentioning

confidence: 50%

Neutrophils Contribute to ER Stress in Lung Epithelial Cells in the Pristane-Induced Diffuse Alveolar Hemorrhage Mouse Model

et al. 2022

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Diffuse alveolar hemorrhage (DAH), although rare, is a life-threatening complication of systemic lupus erythematosus (SLE). Little is known about the pathophysiology of DAH in humans, although increasingly neutrophils, NETosis and inflammatory monocytes have been shown to play an important role in the pristane-induced model of SLE which develops lung hemorrhage and recapitulates many of the pathologic features of human DAH. Using this experimental model, we asked whether endoplasmic reticulum (ER) stress played a role in driving the pathology of pulmonary hemorrhage and what role infiltrating neutrophils had in this process. Analysis of lung tissue from pristane-treated mice showed genes associated with ER stress and NETosis were increased in a time-dependent manner and reflected the timing of CD11b+Ly6G+ neutrophil accumulation in the lung. Using precision cut lung slices from untreated mice we observed that neutrophils isolated from the peritoneal cavity of pristane-treated mice could directly induce the expression of genes associated with ER stress, namely Chop and Bip. Mice which had myeloid-specific deletion of PAD4 were generated and treated with pristane to assess the involvement of PAD4 and PAD4-dependent NET formation in pristane-induced lung inflammation. Specific deletion of PAD4 in myeloid cells resulted in decreased expression of ER stress genes in the pristane model, with accompanying reduction in IFN-driven genes and pathology. Lastly, coculture experiments of human neutrophils and human lung epithelial cell line (BEAS-2b) showed neutrophils from SLE patients induced significantly more ER stress and interferon-stimulated genes in epithelial cells compared to healthy control neutrophils. These results support a pathogenic role of neutrophils and NETs in lung injury during pristane-induced DAH through the induction of ER stress response and suggest that overactivation of neutrophils in SLE and NETosis may underlie development of DAH.

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NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns

Cited by 30 publications

References 72 publications

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

The role of neutrophil extracellular traps in acute lung injury

Neutrophils Contribute to ER Stress in Lung Epithelial Cells in the Pristane-Induced Diffuse Alveolar Hemorrhage Mouse Model

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