NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns
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)...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2021-05-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.147564 |
| _version_ | 1818241433950224384 |
|---|---|
| author | Ranu Surolia Fu Jun Li Zheng Wang Mahendra Kashyap Ritesh Kumar Srivastava Amie M. Traylor Pooja Singh Kevin G. Dsouza Harrison Kim Jean-Francois Pittet Jaroslaw W. Zmijewski Anupam Agarwal Mohammad Athar Aftab Ahmad Veena B. Antony |
| author_facet | Ranu Surolia Fu Jun Li Zheng Wang Mahendra Kashyap Ritesh Kumar Srivastava Amie M. Traylor Pooja Singh Kevin G. Dsouza Harrison Kim Jean-Francois Pittet Jaroslaw W. Zmijewski Anupam Agarwal Mohammad Athar Aftab Ahmad Veena B. Antony |
| author_sort | Ranu Surolia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T13:29:16Z |
| format | Article |
| id | doaj.art-11229075bb154bd8907ed402be32ccab |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T13:29:16Z |
| publishDate | 2021-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-11229075bb154bd8907ed402be32ccab2022-12-22T00:23:06ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-05-01610NETosis in the pathogenesis of acute lung injury following cutaneous chemical burnsRanu SuroliaFu Jun LiZheng WangMahendra KashyapRitesh Kumar SrivastavaAmie M. TraylorPooja SinghKevin G. DsouzaHarrison KimJean-Francois PittetJaroslaw W. ZmijewskiAnupam AgarwalMohammad AtharAftab AhmadVeena B. AntonyDespite 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.https://doi.org/10.1172/jci.insight.147564Pulmonology |
| spellingShingle | Ranu Surolia Fu Jun Li Zheng Wang Mahendra Kashyap Ritesh Kumar Srivastava Amie M. Traylor Pooja Singh Kevin G. Dsouza Harrison Kim Jean-Francois Pittet Jaroslaw W. Zmijewski Anupam Agarwal Mohammad Athar Aftab Ahmad Veena B. Antony NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns JCI Insight Pulmonology |
| title | NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns |
| title_full | NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns |
| title_fullStr | NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns |
| title_full_unstemmed | NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns |
| title_short | NETosis in the pathogenesis of acute lung injury following cutaneous chemical burns |
| title_sort | netosis in the pathogenesis of acute lung injury following cutaneous chemical burns |
| topic | Pulmonology |
| url | https://doi.org/10.1172/jci.insight.147564 |
| work_keys_str_mv | AT ranusurolia netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT fujunli netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT zhengwang netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT mahendrakashyap netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT riteshkumarsrivastava netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT amiemtraylor netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT poojasingh netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT kevingdsouza netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT harrisonkim netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT jeanfrancoispittet netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT jaroslawwzmijewski netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT anupamagarwal netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT mohammadathar netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT aftabahmad netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns AT veenabantony netosisinthepathogenesisofacutelunginjuryfollowingcutaneouschemicalburns |