Dolinay, T and Wu, W and Kaminski, N and Ifedigbo, E and Kaynar, AM and Szilasi, M and Watkins, SC and Ryter, SW and Hoetzel, A and Choi, AMK
(2008)
Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury.
PLoS ONE, 3 (2).
Abstract
Background: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-jun-NH2-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during mechanical ventilation. Methodology and Principle Findings: C57/BL6 wild-type mice and mice genetically deleted for mitogen-activated protein kinase kinase-3 (mkk-3-/-) or c-Jun-NH2-terminal kinase-1 (jnk1-/-) were ventilated, and lung injury parameters were assessed. We demonstrate that mkk3-/- or jnk1-/- mice displayed significantly reduced inflammatory lung injury and apoptosis relative to wild-type mice. Since jnk1-/- mice were highly resistant to ventilator-induced lung injury, we performed comprehensive gene expression profiling of ventilated wild-type or jnk1-/- mice to identify novel candidate genes which may play critical roles in the pathogenesis of ventilator-induced lung injury. Microarray analysis revealed many novel genes differentially expressed by ventilation including matrix metalloproteinase-8 (MMP8) and GAFF45α. Functional characterization of MMP8 revealed that mmp8-/- mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. Conclusion: We demonstrate that mitogen-activated protein kinase pathways mediate inflammatory lung injury during ventilator-induced lung injury. C-Jun-NH2-terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage. © 2008 Dolinay et al.
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| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Dolinay, T | | | | | Wu, W | | | | | Kaminski, N | | | | | Ifedigbo, E | | | | | Kaynar, AM | kaynar@pitt.edu | AMK96 | 0000-0001-8847-0450 | | Szilasi, M | | | | | Watkins, SC | | | | | Ryter, SW | | | | | Hoetzel, A | | | | | Choi, AMK | | | |
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| Contributors: |
| Contribution | Contributors Name | Email | Pitt Username | ORCID |
|---|
| Editor | Cookson, Mark | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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| Date: |
13 February 2008 |
| Date Type: |
Publication |
| Journal or Publication Title: |
PLoS ONE |
| Volume: |
3 |
| Number: |
2 |
| DOI or Unique Handle: |
10.1371/journal.pone.0001601 |
| Schools and Programs: |
School of Medicine > Critical Care Medicine |
| Refereed: |
Yes |
| PubMed ID: |
18270588 |
| Date Deposited: |
18 Jul 2012 20:54 |
| Last Modified: |
22 Jun 2021 10:55 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/12933 |
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