Induction of arginase I and II in bleomycin-induced fibrosis of mouse lung

Abstract

Arginase, which hydrolyzes arginine to urea and ornithine, is a precursor for the synthesis of polyamines and proline, which is abundant in collagen. The supply of proline can be a crucial factor in the process of lung fibrosis. We investigated the induction of arginine metabolic enzymes in bleomycin-induced mouse lung fibrosis. Histological studies and quantification of lung hydroxyproline showed that lung fibrosis develops in up to 14 days after bleomycin treatment. Under these conditions, collagen I mRNA was induced gradually in up to 15 days, and the content of hydroxyproline reached a maximum at 10 days. Arginase I mRNA was undetectable before bleomycin treatment but was induced 5-10 days after this treatment. Arginase I protein was induced at 7 days and remained little changed for up to 10 days and decreased at 14 days. On the other hand, arginase II mRNA that was detectable before treatment was increased gradually for up to 10 days and decreased at 14 days. Arginase II protein began to increase at day 5, increased for up to 10 days, and was decreased at day 14. mRNAs for cationic amino acid transporter-2 and ornithine decarboxylase were induced in a manner similar to that seen with collagen I mRNA. Immunohistochemical analysis showed that arginase I is induced in macrophages, whereas arginase II is induced in various cell types, including macrophages and myofibroblasts, and roughly colocalizes with the collagen-specific chaperone heat shock protein 47. Our findings suggest that arginine metabolic enzymes play an important role in the development of lung fibrosis, at least in mice.

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

“…In support of this, the profibrotic factor TGF-b has been shown to induce arginase activity in mouse lung and fibroblasts [45]. Moreover, increased expression of arginases I and II was closely associated with increased collagen I and hydroxyproline expression in bleomycin-induced lung fibrosis in mice [27,46]. Using inhaled ABH, we now demonstrate that increased arginase activity contributes to allergen-induced fibrosis as well.…”

Gene Expression Profiles Reveal Increased mClca3 (Gob5) Expression and Mucin Production in a Murine Model of Asbestos-Induced Fibrogenesis

“…Arginase II also plays a role in collagen synthesis as was shown in a murine model of bleomycin-induced fibrosis. 33 In addition, Que and colleagues 34 showed the induction of arginase I and II during the fibroproliferative phase of hyperoxic lung injury in rats. The increase in arginase II in our model when peribronchiolar fibrosis (40 days) is observed is consistent with its involvement in repair processes.…”

Crystal structure of human arginase I at 1.29-Å resolution and exploration of inhibition in the immune response

“…As a modulator of NO-dependent macrophage cytotoxicity, arginase I is implicated in the regulation of macrophage activity in wound healing (8) and the suppression of the tumoricidal activity of macrophages (9) and T cells (10). Notably, arginase I is very highly up-regulated in the murine spinal cord during experimental autoimmune encephalomyelitis, an animal model for human multiple sclerosis (11), and it is up-regulated in the inflammatory regions of the asthmatic lung (12)(13)(14).Arginase I in the immune response is also implicated in cancer biology: arginase I is significantly up-regulated and promotes tumor cell growth in breast cancer (15, 16) and colorectal cancer (17). Rodriguez et al (10, 18, 19) recently demonstrated that macrophages stimulated by interleukins 4 and 13 produce high levels of arginase I and cause T-cell anergy by decreasing the expression of the T-cell receptor CD3 chain; furthermore, arginase inhibition blocks the growth of lung carcinoma in a murine model.…”

“…As a modulator of NO-dependent macrophage cytotoxicity, arginase I is implicated in the regulation of macrophage activity in wound healing (8) and the suppression of the tumoricidal activity of macrophages (9) and T cells (10). Notably, arginase I is very highly up-regulated in the murine spinal cord during experimental autoimmune encephalomyelitis, an animal model for human multiple sclerosis (11), and it is up-regulated in the inflammatory regions of the asthmatic lung (12)(13)(14).…”