Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury

Tamara Mirzapoiazova, Jaideep Moitra, Liliana Moreno-Vinasco, Saad Sammani, Jerry R. Turner, Eddie T. Chiang, Carrie Evenoski, Ting Wang, Patrick A. Singleton, Yong Huang, Yves A Lussier, D. Martin Watterson, Steven M. Dudek, Joe GN Garcia

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Acute lung injury (ALI) and mechanical ventilator-induced lung injury (VILI), major causes of acute respiratory failure with el evated morbidity and mortality, are characterized by significant pulmonary inflammation and alveolar/vascular barrier dysfunction. Previous studies highlighted the role of the non-muscle myosin light chain kinase isoform (nmMLCK) as an essential element of the inflammatory response, with variants in the MYLK gene that contribute to ALI susceptibility. To define nmMLCK involvement further in acute inflammatory syndromes, we used two murine models of inflammatory lung injury, induced by either an intratracheal administration of lipopolysaccharide (LPS model) or mechanical ventilation with increased tidal volumes (the VILI model). Intravenous delivery of the membrane-permeant MLC kinase peptide inhibitor, PIK, produced a dose-dependent attenuation of both LPS-induced lung inflammation and VILI (z50% reductions in alveolar/vascular permeability and leukocyte influx). Intravenous injections of nmMLCK silencing RNA, either directly or as cargo within angiotensin-converting enzyme (ACE) antibody-conjugated liposomes (to target the pulmonary vasculature selectively), decreased nmMLCK lung expression (z70% reduction) and significantly attenuated LPS-induced and VILI-induced lung inflammation (z40% reduction in bronchoalveolar lavage protein). Compared with wild-type mice, nmMLCKknockout mice were significantly protected from VILI, with significant reductions in VILI-induced gene expression in biological pathways such as nrf2-mediated oxidative stress, coagulation, p53-signa ling,leukocyte extravasation, and IL-6-signaling. These studies validate nmMLCK as an attractive target for ameliorating the adverse effects of dysregulated lung inflammation.

Original languageEnglish (US)
Pages (from-to)40-52
Number of pages13
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume44
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

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Ventilator-Induced Lung Injury
Myosin-Light-Chain Kinase
Acute Lung Injury
Protein Isoforms
Pneumonia
Leukocytes
Oxidative stress
RNA Isoforms
Peptidyl-Dipeptidase A
Lung
Coagulation
Gene expression
Liposomes
Tidal Volume
Capillary Permeability
Response Elements
Lung Injury
Bronchoalveolar Lavage
Lipopolysaccharides
Mechanical Ventilators

Keywords

  • Endothelial barrier
  • Endotoxin/lipopolysaccharide
  • Lung injury
  • Mice
  • NmMLCK

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury. / Mirzapoiazova, Tamara; Moitra, Jaideep; Moreno-Vinasco, Liliana; Sammani, Saad; Turner, Jerry R.; Chiang, Eddie T.; Evenoski, Carrie; Wang, Ting; Singleton, Patrick A.; Huang, Yong; Lussier, Yves A; Watterson, D. Martin; Dudek, Steven M.; Garcia, Joe GN.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 44, No. 1, 01.01.2010, p. 40-52.

Research output: Contribution to journalArticle

Mirzapoiazova, T, Moitra, J, Moreno-Vinasco, L, Sammani, S, Turner, JR, Chiang, ET, Evenoski, C, Wang, T, Singleton, PA, Huang, Y, Lussier, YA, Watterson, DM, Dudek, SM & Garcia, JGN 2010, 'Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury', American Journal of Respiratory Cell and Molecular Biology, vol. 44, no. 1, pp. 40-52. https://doi.org/10.1165/rcmb.2009-0197OC
Mirzapoiazova, Tamara ; Moitra, Jaideep ; Moreno-Vinasco, Liliana ; Sammani, Saad ; Turner, Jerry R. ; Chiang, Eddie T. ; Evenoski, Carrie ; Wang, Ting ; Singleton, Patrick A. ; Huang, Yong ; Lussier, Yves A ; Watterson, D. Martin ; Dudek, Steven M. ; Garcia, Joe GN. / Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury. In: American Journal of Respiratory Cell and Molecular Biology. 2010 ; Vol. 44, No. 1. pp. 40-52.
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