Cell- and Isoform-Specific Increases in Arginase Expression in Acute Silica-Induced Pulmonary Inflammation

Abstract

Arginase induction was reported in several inflammatory lung diseases, suggesting that this may be a common feature underlying the pathophysiology of such diseases. As little is known regarding arginase expression in silicosis, the induction and cellular localization of arginase was elucidated in lungs of Sprague-Dawley rats 24 hr following exposure to varying doses of silica by intratracheal instillation. Arginase expression was evaluated by activity assay, quantification of arginase I and arginase II mRNA levels using real-time PCR, and immunohistochemistry. Analyses of cells and fluid obtained by bronchoalveolar lavage (BAL) showed that markers of pulmonary inflammation, tissue damage, activation of alveolar macrophages (AM) and NO production were significantly increased by all silica doses. Arginase activity was increased also in AMs isolated from BAL fluid of silica-treated rats. Silica produced 2-and 3-fold increases in arginase activity of whole lung at doses of 1 and 5 mg/100g body weight, respectively. Levels of arginase I mRNA, but not of arginase II mRNA, were similarly elevated. In control lungs, arginase I immunoreactivity was observed only in AMs sparsely dispersed throughout the lung; no iNOS immunoreactivity was detected. In silicatreated lungs, arginase I and iNOS were co-expressed in most AMs that were abundantly clustered at inflammatory foci. The rapid induction of arginase I expression in inflammatory lung cells, similar to induction of arginase in other inflammatory lung diseases, implicates elevated arginase activity as a factor in the development of lung damage following exposure to silica.

Fibrogenic and Redox-Related but not Proinflammatory Genes are Upregulated in Lewis Rat Model of Chronic Silicosis

“…Sod2 is the primary defense against toxicity of superoxide anions generated by oxidative stress (Martin et al 2006), and Arg1 metabolizes arginine and reduces its availability for nitric oxide synthase, leading to reduced production of nitric oxide. Increased Arg1 immunoreactivity was also observed in an animal model of acute silicosis (Poljakovic et al 2007). Our qPCR analysis confirmed the enhanced expression of Arg1 and Sod2 , and Western blot analysis indicated continued progressive increase in Arg1 and Sod2 during the development of sub-chronic silicosis, reaching the highest level at 28 week post-silica inhalation.…”

Caveolin-1 knockout mice exhibit airway hyperreactivity

“…In smooth muscle, including ASM, caveolae contain proteins that regulate [Ca 2ϩ ] i signaling, contraction, and cellular proliferation (7,16,39,40). For example, caveolae in canine ASM express binding proteins for L-type Ca 2ϩ channels and plasma membrane Ca 2ϩ ATPase (8), whereas human ASM caveolae express receptors for agonists such as ACh and histamine, Ca 2ϩ influx mechanisms such as the TRPC channels and Orai1 (41), and force regulatory proteins such as RhoA (22,41).…”

“Of Mice and Men”: Arginine Metabolism in Macrophages

“…In order to perform their full range of functions, macrophage populations exhibit “plasticity” of phenotype ( 52 , 58 ), regardless of whether they are found in vivo or derived in vitro . As macrophages adapt or change their functions, they can simultaneously express markers of M1 and M2 activation, including NOS2 and arginase-1 ( 12 , 59 , 60 ). For example, tissue macrophages (and MDM) from Mycobacterium tuberculosis -infected cynomolgus macaques have been observed to co-express functional NOS and arginase enzymes ( 12 ).…”