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1 Department of Anesthesia and Critial Care, Johns Hopkins Medical Institutions, Baltimore, MD, USA
2 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
3 Department of Environmental Health Sciences, Division of Physiology, Johns Hopkins Medical Institutiions, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: dpearse{at}jhmi.edu.
Ischemia-reperfusion (IR) 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 IR to evaluate the genetic determinants of IR lung injury. An index of pulmonary vascular protein permeability was measured by the ratio of left-to-right lung Evans Blue dye (EBD) of eight inbred mouse strains following 30 min of left lung ischemia and 150 min of reperfusion. The order of strain-specific sensitivity to IR 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 EBD content suggested the presence of contralateral injury because baseline vascular permeability was not different. Lung IR 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 IR 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 IR 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 IR injury.
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