PneumocystisPneumonia Increases the Susceptibility of Mice to Sublethal Hyperoxia

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Abstract
Patients withPneumocystispneumonia often develop respiratory failure after entry into medical care, and one mechanism for this deterioration may be increased alveolar epithelial cell injury. In vitro, we previously demonstrated thatPneumocystisis not cytotoxic for alveolar epithelial cells. In vivo, however, infection withPneumocystiscould increase susceptibility to injury by stressors that, alone, would be sublethal. We examined transient exposure to hyperoxia as a prototypical stress that does cause mortality in normal mice. Mice were depleted of CD4+T cells and inoculated intratracheally withPneumocystis. Control mice were depleted of CD4+T cells but did not receivePneumocystis. After 4 weeks, mice were maintained in normoxia, were exposed to hyperoxia for 4 days, or were exposed to hyperoxia for 4 days followed by return to normoxia. CD4-depleted mice withPneumocystispneumonia demonstrated significant mortality after transient exposure to hyperoxia, while all uninfected control mice survived this stress. We determined that organism burdens were not different. However, infected mice exposed to hyperoxia and then returned to normoxia demonstrated significant increases in inflammatory cell accumulation and lung cell apoptosis. We conclude thatPneumocystispneumonia leads to increased mortality following a normally sublethal hyperoxic insult, accompanied by alveolar epithelial cell injury and increased pulmonary inflammation.

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