Rationale/Methods Little is known regarding the genetic predisposition to the increased vascular permeability and lung inflammation that are cardinal features of acute lung injury (ALI) and mechanical ventilation-induced lung injury (VILI). The comparison of strain-specific responses to high volume mechanical ventilation in rodent models of lung injury is useful in understanding genetic predisposition to ALI/VILI in humans. In the present study, we identified strain-specific differences in susceptibility to high volume mechanical ventilation using an in vivo rat model. Two strains of highly inbred rats, Dahl Salt Sensitive (SS) and Brown Norway (BN), underwent either spontaneous ventilation or high tidal volume ventilation (20 mL/kg, 85 bpm) for two hours. Vascular permeability was measured by tissue Evan's Blue dye (EBD) deposition and bronchoalveolar lavage fluid (BALF) protein concentrations. Lung inflammation was assessed with BALF cell count and differential.
Results There were no significant differences in baseline BALF cell count/differential, BALF protein, or tissue EBD deposition between the two strains. High volume ventilation had no significant effect on BALF cell count or differential in either strain. However, the BN strain rats had a significant increase in both BALF protein (235% increase, p<0.01) and tissue EBD deposition (21% increase, p<0.05) with high tidal volume ventilation. The SS displayed no significant change in either BALF or tissue EBD deposition.
Conclusion Using an in vivo rodent model, we have identified strain-specific differences in susceptibility to VILI that strongly support an important genetic contribution to the development of increased vascular permeability that occurs during ALI. Ongoing genomic studies using parental and consomic rats will allow for the identification of quantitative trait loci (QTLs) and candidate genes important in determining both susceptibility and mechanisms of VILI. NHLBI HL07534.