G‐CSF instillation into rat lungs mediates neutrophil recruitment, pulmonary edema, and hypoxia

Activated neutrophils (PMN) have been implicated in the pathogenesis of adult respiratory distress syndrome (ARDS). Granulocyte colony- stimulating factor (G-CSF) is essential for PMN production and activation of PMN functions. We have recently shown that levels of G-CSF mRNA in a rat model of hemorrhagic shock correlated with severity of shock, PMN infiltration, pulmonary edema, and hypoxia. To determine whether in- creased tissue levels of G-CSF contribute to PMN recruitment and PMN-mediated injury, we instilled G-CSF into the lungs by intratracheal injection. Animals treated with G-CSF became hypoxic, hypo- capnic, and alkalotic and demonstrated increased BAL fluid cellularity compared with control ani- mals. The wet-to-dry ratio increased significantly after G-CSF instillation and peaked at 12 h. Histo- logical examination of the lungs from G-CSF- treated rats revealed marked edema and increased PMN within the interstitium and alveoli. These results indicate that the presence of G-CSF alone in the lung can lead to recruitment of PMN, lung injury, and impaired pulmonary function, suggest- ing that local production of G-CSF may contribute to the development of lung damage and possibly ARDS in the setting of resuscitated hemorrhagic shock. J. Leukoc. Biol. 63: 169-174; 1998. phages, fibroblasts, endothelial cells, and bronchioepithelial cells (5). G-CSF is essential for PMN production and has been shown in vitro and after systemic administration to enhance functional activities of mature neutrophils, including chemo- taxis, phagocytosis, degranulation and protease release, and ROI production. We have recently demonstrated that G-CSF mRNA is produced in the lungs of rats subjected to hemorrhagic shock (6). Bronchial epithelial cells were the major cellular site of G-CSF production in the lung with cells lining the distal bronchiols producing more G-CSF mRNA than cells lining the proximal airways (5). To test the hypothesis that G-CSF protein in the distal airways of the lung will cause PMN recruitment and PMN-mediated injury, we administered G-CSF by intratra- cheal instillation into the lungs of anesthetized rats. G-CSF instillation resulted in increased wet-to-dry ratios, an increase in bronchoalveolar lavage (BAL) fluid cellularity, accumulation of PMN into widened interstitial and alveolar spaces, and hypoxia. These results indicate that the presence of G-CSF in the lung alone is sufficient to recruit PMN and lead to lung injury and suggest that pulmonary production of G-CSF contributes to ARDS.