Relationship of Keratinocyte Growth Factor and Hepatocyte Growth Factor Levels in Rat Lung Lavage Fluid to Epithelial Cell Regeneration after Bleomycin

Abstract

Keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) are known mitogens for normal alveolar Type 2 cells in vitro and in vivo. We wished to determine whether these two growth factors are involved in lung repair after epithelial cell necrosis by determining the levels of each factor in lung lavage fluid collected serially after bleomycin-induced injury , and how these values relate specifically to proliferation of bronchiolar and alveolar epithelial cells. Rats received an intratracheal injection of 1 unit bleomycin in 0.5 ml water and were killed at intervals up to 4 weeks with 1 Ci/g tritiated thymidine injected 1 hour before death. Early necrosis of bronchiolar epithelial (BR) cells and Type 1 alveolar epithelium was followed by an increase in inflammatory cell numbers and high protein levels in bronchoalveolar lavage (BAL) fluids. In addition , the levels of KGF and HGF , measured by enzyme-linked immunosorbent assay in BAL , increased as early as 3 days and peaked at 7-14 days , when KGF was measured at 160 pg/ml (n ‫؍‬ 50) and HGF reached 460 pg/ml (n ‫؍‬ 40). Both values dropped sharply after 2 weeks. Epithelial cell proliferation was quantitated as percentage of labeled cells in autoradiographs of methacrylate sections. Labeling of BR cells predominated in the first week and peaked at 7% at 3 days. Type 2 cell proliferation was delayed somewhat but occurred in 3 to 10 days with a peak of 7% labeled cells at 1 week. The results demonstrate that both HGF and KGF are present in the lung in greatly increased amounts soon after bleomycin-induced epithelial cell necrosis. These high levels are associated with both BR and alveolar epithelial cell proliferation. (Am J Pathol 1999, 155:949 -954)

Keratinocyte growth factor protects epidermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents

“…Interestingly, no difference in the extent of UVB damage was seen in these mice in the absence of exogenous KGF. This finding is consistent with our result that -in contrast to many other situations where KGF expression is upregulated upon epithelial injury (Werner et al, 1992;Zeeh et al, 1996;Baskin et al, 1997;Charafeddine et al, 1999;Adamson and Bakowska, 1999) -enhanced KGF expression upon UV irradiation could be detected neither in murine skin nor in cultured fibroblasts (our unpublished data).…”

Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix

“…Similar changes occur in animal models, including bleomycin-induced pulmonary fibrosis (23,50). This increase in HGF expression is not an epiphenomenon, but is intimately linked to the repair process.…”

Hepatocyte Growth Factor Protects Small Airway Epithelial Cells from Apoptosis Induced by Tumor Necrosis Factor-α or Oxidative Stress

“…SAEC was cultured for 48 h without (lanes 1-4) or with (lanes 5-12) TNF-␣ in the absence (lanes 1-8) or presence (lanes 9 -12) of HGF (40 ng/mL). Nuclear extracts were incubated with (lanes 4, 8, and 12) or without (lanes 1-3, 5-7, and 9 -11) anti-p50 antibody in the absence (lanes 1, 4, and 9) or presence of 100-fold excess of unlabeled consensus (C; lanes 2, 6, and 10) or mismatched (M; lanes 3,4,7,8,11, and 12) NF-B oligonucleotide followed by the addition of 32 P-labeled NF-Bspecific oligonucleotide. (C) Effect of HGF on the NF-B activity after H 2 O 2 treatment.…”

“…Pulmonary mesenchymal cells synthesize and secrete HGF, which has been shown to be involved not only in the formation of bronchoalveolar structure during fetal development, but also in the repair process of injured distal organs such as liver and kidney (7)(8)(9)(10). In the bleomycin-induced lung injury model in rats (11), HGF showed the proliferative effect on type II alveolar epithelial cells, but showed the antiproliferative effect on alveolar macrophages and fibroblasts mainly implicated in the occurrence of fibrotic changes of the lung. In addition, it has recently been shown that endogenous and exogenous HGF protects cardiac myocytes in a rat model of ischemia/reperfusion injury (12) and that the addition of HGF in the culture effectively protects adult rat cardiac myocytes from oxidative stress-induced apoptosis (13).…”