Mechanical Stress and the Induction of Lung Fibrosis via the Midkine Signaling Pathway
RATIONALE: Lung-protective ventilatory strategies have been widely used in patients with acute respiratory distress syndrome (ARDS), but the ARDS mortality rate remains unacceptably high and there is no proven pharmacologic therapy.
OBJECTIVES: Mechanical ventilation can induce oxidative stress and lung fibrosis, which may contribute to high dependency on ventilator support and increased ARDS mortality. We hypothesized that the novel cytokine, midkine (MK), which can be up-regulated in oxidative stress, plays a key role in the pathogenesis of ARDS-associated lung fibrosis.
METHODS: Blood samples were collected from 17 patients with ARDS and 10 healthy donors. Human lung epithelial cells were challenged with hydrogen chloride followed by mechanical stretch for 72 hours. Wild-type and MK gene-deficient (MK(-/-)) mice received two-hit injury of acid aspiration and mechanical ventilation, and were monitored for 14 days.
MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of MK were higher in patients with ARDS than in healthy volunteers. Exposure to mechanical stretch of lung epithelial cells led to an epithelial-mesenchymal transition profile associated with increased expression of angiotensin-converting enzyme, which was attenuated by silencing MK, its receptor Notch2, or NADP reduced oxidase 1. An increase in collagen deposition and hydroxyproline level and a decrease in lung tissue compliance seen in wild-type mice were largely attenuated in MK(-/-) mice.
CONCLUSIONS: Mechanical stretch can induce an epithelial-mesenchymal transition phenotype mediated by the MK-Notch2-angiotensin-converting enzyme signaling pathway, contributing to lung remodeling. The MK pathway is a potential therapeutic target in the context of ARDS-associated lung fibrosis.
| Errataetall: |
CommentIn: Am J Respir Crit Care Med. 2015 Aug 1;192(3):271-2. - PMID 26230229 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:192 |
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| Enthalten in: |
American journal of respiratory and critical care medicine - 192(2015), 3 vom: 01. Aug., Seite 315-23 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Rong [VerfasserIn] |
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| Links: |
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| Themen: |
137497-38-2 |
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| Anmerkungen: |
Date Completed 26.10.2015 Date Revised 09.12.2020 published: Print CommentIn: Am J Respir Crit Care Med. 2015 Aug 1;192(3):271-2. - PMID 26230229 Citation Status MEDLINE |
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| doi: |
10.1164/rccm.201412-2326OC |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM24873203X |
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| 100 | 1 | |a Zhang, Rong |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mechanical Stress and the Induction of Lung Fibrosis via the Midkine Signaling Pathway |
| 264 | 1 | |c 2015 | |
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| 500 | |a Date Completed 26.10.2015 | ||
| 500 | |a Date Revised 09.12.2020 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: Am J Respir Crit Care Med. 2015 Aug 1;192(3):271-2. - PMID 26230229 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a RATIONALE: Lung-protective ventilatory strategies have been widely used in patients with acute respiratory distress syndrome (ARDS), but the ARDS mortality rate remains unacceptably high and there is no proven pharmacologic therapy | ||
| 520 | |a OBJECTIVES: Mechanical ventilation can induce oxidative stress and lung fibrosis, which may contribute to high dependency on ventilator support and increased ARDS mortality. We hypothesized that the novel cytokine, midkine (MK), which can be up-regulated in oxidative stress, plays a key role in the pathogenesis of ARDS-associated lung fibrosis | ||
| 520 | |a METHODS: Blood samples were collected from 17 patients with ARDS and 10 healthy donors. Human lung epithelial cells were challenged with hydrogen chloride followed by mechanical stretch for 72 hours. Wild-type and MK gene-deficient (MK(-/-)) mice received two-hit injury of acid aspiration and mechanical ventilation, and were monitored for 14 days | ||
| 520 | |a MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of MK were higher in patients with ARDS than in healthy volunteers. Exposure to mechanical stretch of lung epithelial cells led to an epithelial-mesenchymal transition profile associated with increased expression of angiotensin-converting enzyme, which was attenuated by silencing MK, its receptor Notch2, or NADP reduced oxidase 1. An increase in collagen deposition and hydroxyproline level and a decrease in lung tissue compliance seen in wild-type mice were largely attenuated in MK(-/-) mice | ||
| 520 | |a CONCLUSIONS: Mechanical stretch can induce an epithelial-mesenchymal transition phenotype mediated by the MK-Notch2-angiotensin-converting enzyme signaling pathway, contributing to lung remodeling. The MK pathway is a potential therapeutic target in the context of ARDS-associated lung fibrosis | ||
| 650 | 4 | |a Controlled Clinical Trial | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a angiotensin-converting enzyme | |
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| 650 | 4 | |a mechanical ventilation | |
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| 700 | 1 | |a Wu, Sulong |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Alice Aili |e verfasserin |4 aut | |
| 700 | 1 | |a Islam, Diana |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Pu |e verfasserin |4 aut | |
| 700 | 1 | |a Ghazarian, Mirna |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Wenmei |e verfasserin |4 aut | |
| 700 | 1 | |a Spieth, Peter M |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Dingyan |e verfasserin |4 aut | |
| 700 | 1 | |a Khang, Julie |e verfasserin |4 aut | |
| 700 | 1 | |a Mo, Hongyin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiaoqing |e verfasserin |4 aut | |
| 700 | 1 | |a Uhlig, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Mingyao |e verfasserin |4 aut | |
| 700 | 1 | |a Laffey, John |e verfasserin |4 aut | |
| 700 | 1 | |a Slutsky, Arthur S |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yimin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Haibo |e verfasserin |4 aut | |
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