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The aim of the study was to determine whether sex-related differences exist in immune response to inhalation lung injury. C57BL/6 mice were exposed to Cl₂ gas (500 ppm for 15, 20, or 30 min). Results showed that male mice have higher rates of mortality and lung injury than females. The binding of the chemokine ligand C-X-C motif chemokine 12 (CXCL12), also called stromal-derived-factor-1 (SDF-1), to the C-X-C chemokine receptor type 4 (CXCR4) on lung cells promotes the migration of leukocytes from circulation to lungs. Therefore, the hypothesis was that elevated SDF-1/CXCR4 signaling mediates exaggerated immune response in males. Plasma, blood leukocytes, and lung cells were collected from mice post-Cl₂ exposure. Plasma levels of SDF-1 and peripheral levels of CXCR4 in lung cells were higher in male vs. female mice post-Cl₂ exposure. Myeloperoxidase (MPO) and elastase activity was significantly increased in leukocytes of male mice exposed to Cl₂. Lung cells were then ex vivo treated with SDF-1 (100 ng/mL) in the presence or absence of the CXCR4 inhibitor, AMD3100 (100 nM). SDF-1 significantly increased migration, MPO, and elastase activity in cells obtained from male vs. female mice post-Cl₂ exposure. AMD3100 attenuated these effects, suggesting that differential SDF-1/CXCR4 signaling may be responsible for sex-based disparities in the immune response to inhalation lung injury.