Journal
TRANSLATIONAL RESEARCH
Volume 151, Issue 3, Pages 141-153Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.trsl.2007.12.008
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Funding
- NHLBI NIH HHS [P50 HL 73994, PPG HL 50864, P50 HL073994] Funding Source: Medline
- NIDDK NIH HHS [R01 DK068271-04, R01 DK068271, DK61931, R01 DK061931, R01 DK061931-08] Funding Source: Medline
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We have generated genetically engineered mice that are uniquely susceptible to lipopolysacchadde (LPS)-induced and mechanical ventilation-induced lung injury in a sex-specific and age-specific manner. These mice express a nonmuscle isoform of the myosin light chain kinase gene (nmMLCK2) targeted to the endothelium. Homozygous mice have significantly reduced fecundity and litter survival until weaning, and they are initially growth delayed but eventually exceed the size of wild-type littermates. Mice at all ages show increased protein transport across the lung border; however, the phenotype is most discernible in 8-12-week-old male mice. When subjected to a clinically relevant LPS-induced lung injury model, 8-12-week-old young females and 30-36-week-old males seem to be the most significantly injured group. In contrast, 30-36-week-old males remain the most significantly injured group when mechanically ventilated at high tidal volumes, which is a clinically relevant model of mechanical stress lung injury. These data reveal that nmMLCK2 overexpression in the endothelium exacerbates lung injury in vivo in a sexually dimorphic and age-dependent manner.
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