A transgenic mouse with vascular endothelial over-expression of the non-muscle myosin light chain kinase-2 isoform is susceptible to inflammatory lung injury: role of sexual dimorphism and age.
We have generated genetically engineered mice that are uniquely susceptible to lipopolysaccharide (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 barrier; 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.
Moitra
Jaideep
J
Department of Medicine, University of Chicago, Chicago, Il 60637-1470, USA.
Evenoski
Carrie
C
Sammani
Saad
S
Wadgaonkar
Raj
R
Turner
Jerrold R
JR
Ma
Shwu Fan
SF
Garcia
Joe G N
JG
D000367:Age Factors; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D012121:Respiration, Artificial / Q000009:adverse effects; D012727:Sex Characteristics; D013314:Stress, Mechanical
D007527:Isoenzymes; D008070:Lipopolysaccharides; D009219:Myosin-Light-Chain Kinase