TY - JOUR
T1 - Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury
AU - Mirzapoiazova, Tamara
AU - Moitra, Jaideep
AU - Moreno-Vinasco, Liliana
AU - Sammani, Saad
AU - Turner, Jerry R.
AU - Chiang, Eddie T.
AU - Evenoski, Carrie
AU - Wang, Ting
AU - Singleton, Patrick A.
AU - Huang, Yong
AU - Lussier, Yves A.
AU - Watterson, D. Martin
AU - Dudek, Steven M.
AU - Garcia, Joe G.N.
PY - 2010/1/1
Y1 - 2010/1/1
N2 - 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.
AB - 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.
KW - Endothelial barrier
KW - Endotoxin/lipopolysaccharide
KW - Lung injury
KW - Mice
KW - NmMLCK
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U2 - 10.1165/rcmb.2009-0197OC
DO - 10.1165/rcmb.2009-0197OC
M3 - Article
C2 - 20139351
AN - SCOPUS:78650649946
SN - 1044-1549
VL - 44
SP - 40
EP - 52
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 1
ER -