The female gender protects against pulmonary injury after trauma hemorrhagic shock

Abstract

Background: Previously, we have documented that lung injury after trauma-hemorrhagic shock (T/HS) is related to gut injury and that females are more resistant to T/HS-induced lung injury than males. However, it is not known if the estrus cycle stage at the time of injury influences the female rat's resistance to T/HS-induced lung injury. Therefore, the goal of this study was to determine if the protective effect of the female gender on lung injury after T/HS is estrus cycle stage-specific. To test this hypothesis, female rats were subjected to trauma (laparotomy) and hemorrhagic shock (T/HS) during different stages of the estrus cycle. Female animals subjected to trauma with sham hemorrhagic shock served as the control.

Methods: Female Sprague-Dawley rats during the proestrus, estrus, metestrus, or diestrus stages of the menstrual cycle were subjected to a midline laparotomy (trauma) and either hemorrhagic shock (MAP = 30 mm Hg x 90 min) or sham shock. The total volume of blood necessary to induce and maintain the shock state was recorded. At the end of the shock period, the animals were resuscitated with their shed blood. At 6 h postresuscitation, the animals were sacrificed and lung permeability was measured using the Evans blue dye technique and by determining the bronchoalveolar (BALF) to plasma protein ratio. Additionally, pulmonary leukosequestration was quantitated by measuring pulmonary myeloperoxidase levels.

Results: T/HS-induced lung injury and increased pulmonary leukosequestration were not observed in female rats in the proestrus or estrus stages of the menstrual cycle. In contrast, pulmonary permeability was increased significantly in the diestrus stage animals after T/HS. That is, the diestrus females subjected to T/HS had increased pulmonary permeability to Evans blue dye than sham or T/HS proestrus, estrus, and metestrus rats (6.49 +/- 1.33% versus 1.7 +/- 0.87%, 1.57 +/- 0.54%, 1.78 +/- 0.82%, 3.33 +/- 0.68%, p < 0.01, respectively). Similar results were obtained with the BALF protein/plasma protein ratio (0.15 +/- 0.017 versus 0.09 +/- 0.009, 0.09 +/- 0.03, 0.08 +/- 0.022, 0.11 +/- 0.029 p < 0.05, respectively). Although the T/HS metestrus rats had mildly increased lung permeability, this increase in T/HS-lung permeability did not reach statistical significance. Pulmonary myeloperoxidase levels after T/HS displayed a similar trend, with diestrus rats subjected to T/HS having the highest level of MPO (p < 0.05 versus sham or T/HS proestrus and estrus but not metestrus groups). Linear regression analysis of MPO versus Evans blue dye leak revealed a significant correlation between pulmonary neutrophil sequestration and lung leak (r = 0.9549; p < 0.0001).

Conclusion: Protection against T/HS-induced lung injury was greatest during the estrus and proestrus stages of the menstrual cycle and decreased with progression to diestrus. During the diestrus stage of the menstrual cycle when gonadal hormone levels are lowest, the rats are more sensitive to T/HS-induced lung injury, indicating that gonadal hormones modulate T/HS-induced lung injury.