Strain-specific differences in sensitivity to ischemia-reperfusion lung injury in mice.
Ischemia-reperfusion (I/R) lung injury is characterized by increased pulmonary endothelial permeability and edema, but the genetic basis for this injury is unknown. We utilized an in vivo mouse preparation of unilateral lung I/R to evaluate the genetic determinants of I/R lung injury. An index of pulmonary vascular protein permeability was measured by the ratio of left-to-right lung Evans blue dye of eight inbred mouse strains after 30 min of left lung ischemia and 150 min of reperfusion. The order of strain-specific sensitivity to I/R lung injury was BALB/c < SJL/J < CBA/J < C57BL/6J < 129/J < A/J < C3H/H3J < SWR/J. The reciprocal F1 offspring of the BALB/c and SWR/J progenitor strains had intermediate phenotypes but a differing variance. A similar pattern of right lung Evans blue dye content suggested the presence of contralateral injury because baseline vascular permeability was not different. Lung I/R injury was attenuated by NADPH oxidase inhibition, indicating a role for NADPH oxidase-derived reactive oxygen species (ROS). There was no strain-dependent difference in lung NADPH oxidase expression. Strain-related differences in zymosan-stimulated neutrophil ROS production did not correlate with I/R lung injury in that neutrophil ROS production in SWR/J mice was greater than C57BL/6J but not different from BALB/c mice. These data indicate the presence of a genetic sensitivity to lung I/R injury that involves multiple genes including a maternal-related factor. Although neutrophil-derived ROS production is also modulated by genetic factors, the pattern did not explain the genetic sensitivity to lung I/R injury.
Dodd-o
Jeffrey M
JM
Department of Anesthesia and Critical Care, School of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287-9106, USA. jdoddo@jhmi.edu
Hristopoulos
Maria L
ML
Welsh-Servinsky
Laura E
LE
Tankersley
Clarke G
CG
Pearse
David B
DB
D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D019255:NADPH Oxidases / Q000235:genetics / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics* / Q000503:physiopathology*; D013045:Species Specificity; D013997:Time Factors; D015054:Zymosan / Q000494:pharmacology
D017382:Reactive Oxygen Species; D015054:Zymosan; D019255:NADPH Oxidases