Effect of granulocyte colony-stimulating factor on acute lung injury in the rat.

Abstract

The effect of G-CSF pretreatment on experimental acute lung injury was studied in Sprague-Dawley rats receiving one of the following treatments: (1) G-CSF 50 micrograms/kg subcutaneously twice daily beginning 2 d prior to being killed; (2) ANTU 50 mg/kg intraperitoneally; (3) ANTU+G-CSF 50, 25, or 12.5 micrograms/kg; (4) HCl 0.6 ml of a 0.1 N solution intratracheally; (5) HCl+G-CSF 50 or 25 micrograms/kg; (6) control solutions. Lung injury was quantified by measurement of lung wet/dry weights, by histopathologic scoring, and by measurement of fluid flux during ex vivo perfusion. G-CSF pretreatment elevated the baseline blood neutrophil counts as much as 6-fold compared with Control, and it increased the numbers of lung neutrophils and caused a mild histologic lung injury, but it did not significantly alter wet/dry weight ratios or fluid flux. ANTU alone and HCl alone caused a moderate histologic lung injury, increased wet/dry weight ratio, and resulted in a small increase in flux. The combination injuries, ANTU+G-CSF and HCl+G-CSF, caused a more severe lung injury manifested by increased wet/dry weight ratios and increase in flux when compared with ANTU alone and HCl alone, respectively. We conclude that pretreatment with G-CSF potentiates ANTU- and HCl-induced lung injury in non-neutropenic rats. The potential for G-CSF to aggravate acute lung injury in patients remains speculative.

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

“…Systemic administration of G-CSF has been demonstrated to reduce morbidity and mortality in animal models of infection [4,18,19]. Furthermore, pretreatment of animals with G-CSF reduces mortality following systemic LPS challenge [20][21][22][23].…”

“…The beneficial effect of systemic G-CSF in these settings most likely results from G-CSF-induced neutrophilia and increased PMN function, which enhances innate immunity to infections as well as improves PMN-mediated clearance of LPS. In contrast to the effects of systemic G-CSF on a systemic lipopolysaccharide challenge, systemic G-CSF pretreatment worsens pulmonary damage induced by intratracheal instillation of lipopolysaccharide [24] or acid [4] as a consequence of increased PMN recruitment [4,16]. In addition, PMN that have been primed in vivo by G-CSF demonstrate enhanced release of oxygen radicals and proteases that can cause endothelial cell damage [14,15].…”

“…Activated neutrophils (PMN) have been implicated in the pathogenesis of ARDS during sepsis or shock [1]. PMN adhere to vascular endothelium and migrate into lung interstitium and alveolar spaces [2], causing endothelial and epithelial cell damage [3] through production of reactive oxygen intermediates (ROI) and the release of lysosomal proteases [4]. A variety of chemical mediators of inflammation as well as cytokines have been demonstrated to prime or activate PMN in vitro, including granulocyte colony-stimulating factor (G-CSF).…”

Effects of Granulocyte Colony-Stimulating Factor (G-CSF) on Bleomycin-Induced Lung Injury of Varying Severity

“…In those studies, we evaluated the effects of G-CSF on severe lung injury in rats that developed DAD and subsequent pulmonary fibrosis. However, the effects of G-CSF on experimental lung injury with varying severity have not been examined (20,(23)(24)(25)41).…”

Elevated serum and bronchoalveolar lavage fluid levels of interleukin 8 and granulocyte colony‐stimulating factor associated with the acute chest syndrome in patients with sickle cell disease

“…G-CSF has been shown to be produced during acute lung injury in various settings (Tazi et al, 1991;Terashima et al, 1994). In animal models, G-CSF administration exacerbates acute lung injury owing to endotoxin and increases extraalveolar lung water (Sakuma et al, 1994;Terashima et al, 1994;King et al, 1995). In a similar observation, a patient with sickle cell disease developed ACS after exogenous administration of G-CSF (Abboud et al, 1998).…”