Amphiregulin attenuates bleomycin-induced pneumopathy in mice

Abstract

Amphiregulin, an EGF receptor (EGFR) ligand, is essential for epithelial development in various organs. A recent report suggested that amphiregulin acts as a protective factor in a liver injury model. Little is known about the roles of amphiregulin in lung injury and pulmonary fibrosis. The purpose of the present study was to investigate the role of amphiregulin in an experimental model of bleomycin-induced pneumopathy in mice. C57BL/6 mice were administered a bleomycin hydrochloride solution intratracheally. Recombinant human amphiregulin was injected intraperitoneally at 6, 8, 10, and 12 days after the bleomycin instillation. The grades of inflammation and fibrosis were assessed histologically and biochemically, and the numbers of apoptotic cells were counted after TdT-mediated dUTP nick end labeling (TUNEL) staining in the lung tissues. We also examined downstream survival signals of EGFR, namely phosphorylated Akt and phosphorylated Erk, in lung tissues by Western blotting analysis and immunohistochemistry. Expression of intrinsic amphiregulin was increased in murine lung tissues after bleomycin instillation. Administration of recombinant amphiregulin improved the survival rate and suppressed the degrees of inflammation and fibrosis and the number of TUNEL-positive cells in lung tissues. Amphiregulin treatment enhanced the activation of Akt and Erk in lung epithelial cells. Amphiregulin may play a protective role in bleomycin-induced pneumopathy in mice, probably through the activation of survival signals. Administration of amphiregulin may be a novel therapeutic strategy against lung injury and fibrosis.

Diacetyl Induces Amphiregulin Shedding in Pulmonary Epithelial Cells and in Experimental Bronchiolitis Obliterans

“…Recent in vitro studies have demonstrated increased AREG shedding from pulmonary epithelial cells after exposure to CSE, and particulate matter (PM), including diesel exhaust (10)(11)(12), in the acute setting similar to our in vitro results. Increased pulmonary AREG levels have also been reported in animal models of acute and chronic fibrotic lung disease, including transforming growth factor-b transgenic models (16) and bleomycin-induced lung fibrosis similar to our in vivo results (14). In addition, selective injury to the epithelial Clara cells through naphthalene or transgenic manipulation also led to an up-regulation of AREG transcript after epithelial cell injury (13).…”

“…In the case of bleomycin-induced lung fibrosis, exogenous AREG ameliorated fibrosis (14), whereas, in the case of transforming growth factorb-induced lung fibrosis, inhibition of AREG through siRNA or small molecule inhibitors reduced fibrosis (16). Furthermore, EGFR inhibition significantly reduced bleomycin-induced fibrosis (20).…”

“…AREG shedding has been reported after exposure of human bronchial epithelial cells to several toxic insults, such as diesel exhaust and cigarette smoke extract (CSE) (10)(11)(12). In addition, in vivo studies have demonstrated that AREG transcript is increased in models of bleomycin-induced lung fibrosis and naphthalene-induced epithelial Clara cell injury (13,14).…”

Lung Tumor-Associated Dendritic Cell-Derived Amphiregulin Increased Cancer Progression

“…AKT has been reported to act as an important factor in amphiregulin-mediated cell survival and migration (32,33). In our study, we found that treating A549 and H460 cells with TADC-CM or amphiregulin dramatically increases the activation of AKT.…”

Amphiregulin, an Epidermal Growth Factor Receptor Ligand, Plays an Essential Role in the Pathogenesis of Transforming Growth Factor-β-induced Pulmonary Fibrosis

“…In support of this notion, the use of gefitinib, a EGFR blocker, significantly inhibits bleomycin-induced pulmonary fibrosis (22). On the other hand, Fukumoto et al (43) showed that administration of rAR suppressed bleomycin-induced pulmonary inflammation and fibrosis, suggesting a potential protective role of AR in tissue fibrosis. These potentially contradictory results may simply reflect inherent differences in target organs, cellular compartments, or the nature of injury between different experimental settings.…”