NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns
| Autor: | Jaroslaw W. Zmijewski, K.G. Dsouza, Anupam Agarwal, Mahendra Kashyap, Jean-Francois Pittet, Pooja Singh, Ritesh K. Srivastava, Amie M. Traylor, Zheng Wang, Aftab Ahmad, Veena B. Antony, Mohammad Athar, Harrison Kim, Ranu Surolia, Fu Jun Li |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Pulmonology Neutrophils Acute Lung Injury Chemical burn Lung injury Extracellular Traps Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Protein-Arginine Deiminase Type 4 Burns Chemical medicine Animals Barrier function Molecular pathology business.industry General Medicine Neutrophil extracellular traps respiratory system medicine.disease respiratory tract diseases Mice Inbred C57BL Endothelial stem cell Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Immunology Toxicity Female business Intracellular Research Article |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.147564 |
| Popis: | Despite the high morbidity and mortality among patients with extensive cutaneous burns in the intensive care unit due to the development of acute respiratory distress syndrome, effective therapeutics remain to be determined. This is primarily because the mechanisms leading to acute lung injury (ALI) in these patients remain unknown. We test the hypothesis that cutaneous chemical burns promote lung injury due to systemic activation of neutrophils, in particular, toxicity mediated by the deployment of neutrophil extracellular traps (NETs). We also demonstrate the potential benefit of a peptidyl arginine deiminase 4 (PAD4) inhibitor to prevent NETosis and to preserve microvascular endothelial barrier function, thus reducing the severity of ALI in mice. Our data demonstrated that phenylarsine oxide (PAO) treatment of neutrophils caused increased intracellular Ca2+-associated PAD4 activity. A dermal chemical burn by lewisite or PAO resulted in PAD4 activation, NETosis, and ALI. NETs disrupted the barrier function of endothelial cells in human lung microvascular endothelial cell spheroids. Citrullinated histone 3 alone caused ALI in mice. Pharmacologic or genetic abrogation of PAD4 inhibited lung injury following cutaneous chemical burns. Cutaneous burns by lewisite and PAO caused ALI by PAD4-mediated NETosis. PAD4 inhibitors may have potential as countermeasures to suppress detrimental lung injury after chemical burns. |
| Databáze: | OpenAIRE |
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