OBJECTIVE

To test the hypothesis that therapeutic hypercapnia enhances the proinflammatory responses to endotoxemia in the lung and spleen of rats.

METHODS

Prospective randomized study.

METHODS

Hospital research institute.

METHODS

Forty-eight adult male rats.

METHODS

Rats were randomly assigned for a 24-hr period to four breathing groups (n = 11/group), including air (controls), normoxic air with 5% CO2 (therapeutic hypercapnia), air and endotoxemia (5 mg/kg endotoxin), and therapeutic hypercapnia with endotoxemia. After euthanasia, the lung and spleen were removed for pro- and anti-inflammatory cytokine analyses and pulmonary histology evaluation. Four additional rats were used to examine changes in gas exchange and acid-base balance during exposure to therapeutic hypercapnia with and without endotoxemia before and at 4, 12, and 24 hrs into the study, using a permanently catheterized femoral artery.

RESULTS

The ratios of proinflammatory cytokines (interleukin-1β [IL-1β] and IL-6) and an anti-inflammatory cytokine (IL-10) in the lungs and spleen were used as indices of inflammatory status. The wet-weight to dry-weight ratios, histologic changes in lung interstitial inflammation, and alveolar structures were used as indices of endotoxin-induced acute lung injury. IL-1β and IL-6 expression was significantly high in the lung of therapeutic hypercapnia-treated endotoxemic rats compared to the lung of rats subjected to only endotoxemia (p < .05 and p < .001, respectively). In the spleen, therapeutic hypercapnia-treated endotoxemic rats had low expression of IL-1β and IL-6 compared to rats subjected to only endotoxemia (p>> .05 and p < .001). Therapeutic hypercapnia following endotoxemic challenge was associated with a proinflammatory response in the lung and an anti-inflammatory response in spleen, as assessed by the ratios of IL-1β and IL-6 to IL-10. The wet-weight to dry-weight ratio and the interstitial space were significantly increased only in therapeutic hypercapnia-treated endotoxemic rats (p < .05). The alveolar-septal thickness was significantly increased by 21% in endotoxemic rats (p < .001) and by 33% in therapeutic hypercapnia-treated endotoxemic rats (p < .001).

CONCLUSIONS

A 24-hr exposure to therapeutic hypercapnia in endotoxin-stimulated, spontaneously breathing rats is associated with a proinflammatory immune response in the lung and anti-inflammatory response in the spleen as well as an increase in certain histologic indices of endotoxin-induced lung injury.