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

Abstract

We evaluated the effects of granulocyte colony-stimulating factor (G-CSF) on bleomycin (BLM)-induced lung injury that developed diffuse alveolar damage and subsequent pulmonary fibrosis (PF) of varying severity. G-CSF (100 µg/kg/day) was administered subcutaneously to BLM (0.2, 20, 2,000 µg)-treated or -untreated rats for 3 or 14 days. In the BLM 0.2 µg group, slight alveolar mononuclear cell infiltration was observed, although PF was not noted. In the BLM 20-µg and 2,000-µg groups, diffuse alveolar damage along with neutrophil infiltration and subsequent PF were observed. In the saline + G-CSF group and BLM 0.2 µg + G-CSF group, a marked increase in the number of alkaline phosphatase (ALP)-positive neutrophils was noted in the alveolar capillaries, although there was neither neutrophil infiltration in alveoli nor exacerbation of lung injury. In the BLM 20 µg + G-CSF and BLM 2,000 µg + G-CSF groups, an exacerbation of lung injury along with an increase in the number of ALP-positive neutrophils in the alveoli was observed. These results indicate that the administration of G-CSF to rats with slight lung injury bearing no PF does not exacerbate the lung injury. The exacerbating effects of G-CSF seem to be associated not only with the marked infiltration of activated neutrophils but also with the severity of underlying lung injury.

Effects of erlotinib on lung injury induced by intratracheal administration of bleomycin (BLM) in rats

“…Marked damage in the epithelial basement membrane may cause pulmonary fibrosis. In our experiments, BLM (0.1 or 0.6 mg/100 μl)-treated animals showed lung histopathology such as DAD and subsequent pulmonary fibrosis with slight or moderate severity which were similar to those previously reported (Adachi et al, 2003;Chandler et al, 1983;Thrall et al, 1979).…”

“…Scores of lung fibrosis ("Ashcroft score") for BLM-treated control groups were lower in the ICR mouse treated with 5 mg/kg of BLM (average point: 1.2) and higher in the C57BL/6 mouse treated with 3 mg/kg of BLM (average point: 2.4). It is known that the severity of pulmonary lesions in BLM-treated rats would influence the evaluation of BLM-induced lung injury models (Adachi et al, 2003;Okazaki et al, 2001). However, the effects of EGFR-TKIs on lung injury with varying severity have not been examined under the same experimental conditions.…”

“…Measurement of the lung lesion density was done according to the method described by Mautz et al (1988) and Adachi et al (2003). Briefly, HE-stained sections were viewed under a light microscope at a total magnification of ×100.…”

“…Score of lung fibrosis was assessed semi-quantitatively according to the method of Ashcroft et al (1988) and Adachi et al (2003) ("Ashcroft score"). Briefly, lung fibrosis was scored on a scale from 0 to 8 by examining all the parenchyma of each specimen (2 sections/animal) at a magnification of ×100.…”

“…Intratracheal administration of BLM in rats has been widely used to produce a model to study the mechanisms of development and repair in lung injury, especially of pulmonary fibrosis (Chandler et al, 1983;Hay et al, 1991;Kawamoto and Fukuda, 1990;Lazenby et al, 1990;Thrall et al, 1979;Usuki and Fukuda, 1995). Furthermore, rat model can induce lung injury with varying severity (Adachi et al, 2003). The development of pulmonary fibrosis induced by BLM-administration can be divided into the following 3 phases: acute injury of lung cells including alveolar and bronchial epithelium, inflammatory response with infiltration of leucocytes, and fibrogenic response (Adachi et al, 2001;Yara et al, 2001).…”