MLCK210 gene knockout or kinase inhibition preserves lung function following endotoxin-induced lung injury in mice

Janet L. Rossi, Anastasia V. Velentza, David M. Steinhorn, D. Martin Watterson, Mark S. Wainwright

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Barrier dysfunction, involving the endothelium or epithelium, is implicated in the pathophysiology of many disease states, including acute and ventilator-associated lung injury. Evidence from cell culture, in vivo and clinical studies, has identified myosin light chain kinase as a drug discovery target for such diseases. Here, we measured disease-relevant end points to test the hypothesis that inhibition of myosin light chain kinase is a potential therapeutic target for treatment of barrier dysfunction resulting from acute lung injury. We used a combined gene knockout and chemical biology approach with an in vivo intact lung injury model. We showed that inhibition of myosin light chain kinase protects lung function, preserves oxygenation, prevents acidosis, and enhances survival after endotoxin exposure with subsequent mechanical ventilation. This protective effect provided by the small molecule inhibitor of myosin light chain kinase is present when the inhibitor is administered during a clinically relevant injury paradigm after endotoxin exposure. Treatment with inhibitor confers additional protection against acute lung injury to that provided by a standard protective mode of ventilation. These results support the hypothesis that myosin light chain kinase is a potential therapeutic target for acute lung injury and provide clinical end points of arterial blood gases and pulmonary compliance that facilitate the direct extrapolation of these studies to measures used in critical care medicine.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume292
Issue number6
DOIs
StatePublished - Jun 2007
Externally publishedYes

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Myosin-Light-Chain Kinase
Gene Knockout Techniques
Lung Injury
Endotoxins
Phosphotransferases
Acute Lung Injury
Lung
Lung Compliance
Drug Discovery
Mechanical Ventilators
Therapeutics
Critical Care
Acidosis
Artificial Respiration
Endothelium
Ventilation
Epithelium
Cell Culture Techniques
Gases
Medicine

Keywords

  • Acute respiratory distress syndrome
  • Endothelium
  • Oxygenation
  • Protein kinase

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

MLCK210 gene knockout or kinase inhibition preserves lung function following endotoxin-induced lung injury in mice. / Rossi, Janet L.; Velentza, Anastasia V.; Steinhorn, David M.; Watterson, D. Martin; Wainwright, Mark S.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 292, No. 6, 06.2007.

Research output: Contribution to journalArticle

Rossi, Janet L. ; Velentza, Anastasia V. ; Steinhorn, David M. ; Watterson, D. Martin ; Wainwright, Mark S. / MLCK210 gene knockout or kinase inhibition preserves lung function following endotoxin-induced lung injury in mice. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2007 ; Vol. 292, No. 6.
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