br COPD As in asthma also in

COPD As in asthma, also in COPD, increased expression of arginase has been reported, and tobacco smoke may increase expression of arginase in human subjects [46, 47]. Increased ADMA levels have also been reported in COPD, and both the increased expression of arginase and ADMA contribute to remodeling and inflammation, via both NO-dependent and NO-independent pathways [48, 49, 50•]. Accordingly, arginase inhibition protects against the development of COPD-like inflammation and remodeling in a guinea pig model of COPD [49]. Inhibition of NO production appears to not only regulate local airway inflammation, remodeling and reactivity but is a key regulatory mechanism in cardiovascular changes in COPD as well. Local hypoxia in tissues promotes arginase activity, and represses vasodilating NO production [51, 52]. In the lung, this mechanism contributes to pulmonary hypertension and arginase inhibition protects against the development of pulmonary hypertension and right cardiac remodeling [39, 49]. Likewise, hypoxia in left heart failure drives arginase expression by endothelial cells, which plays a clear role in repressing cardiac contractility and recovery from ischemia [53, 54]. Accordingly, inhibition of arginase promotes cardiac contractility and improves cardioprotection after injury [55]. Such a mechanism may also contribute to cerebrovascular disease, which is often found as a co-morbidity in patients with COPD [24]. NO is critical in blood flow regulation in the L-Phenylephrine sale [56]. Therefore, increased arginase expression may lead to vasoconstriction, increasing susceptibility to stroke [57]. In support, arginase 2 deficient mice have improved cerebral blood flow after brain injury [58]. In addition, ADMA is considered a prime biomarker and driver of impaired cerebral blood flow and stroke [59, 60, 61]. Though not directly related to arginase, ADMA expression is increased in smokers and shunts arginine to the arginase pathway [], providing a clear mechanistic link between increases in ADMA and arginase activity. Surprisingly little data is available on pharmacological arginase inhibition and its impact on cerebrovascular disease, although clearly such studies would be of considerable interest. In COPD and, as indicated above, also in asthma, several metabolic changes occur that impact on systemic co-morbidities in COPD such as muscle wasting, osteoporosis and type II diabetes [17, 24]. It is not fully clear how changes in arginase expression in COPD contribute to each of these co-morbidities specifically, although general relationships between arginase and nitric oxide metabolism on the one hand and muscle wasting, osteoporosis and type II diabetes have been reported. Tumor necrosis factor (TNF) driven nuclear factor-κB activation underlies muscle wasting [62] and is inhibited by NO mediated S-nitrosylation of p65 and inhibitor of NF-κB kinase [63]. Increased arginase activity in COPD may suppress this, leading to enhanced p65 activation. De-repression of NO-mediated anti-inflammatory effects and endothelial cell function due to elevated arginase activity may also play a role in fatty acid driven changes in insulin sensitivity and obesity [64]. Thus, increased expression of arginase has been reported in obese subjects in comparison to normal weight subjects [51, 65] and arginase overexpression has been shown to drive eNOS uncoupling in mice aortas in response to overweight []. Furthermore, arginase inhibition restores endothelial dysfunction, hepatic abnormalities and adipose tissue inflammation (interleukin-6, TNF-α, M1 macrophage counts) [67, 68•, 69] in animal models. Arginase is also abundantly expressed in bone, and streptozocin-induced diabetes was associated with reductions in bone mass and bone mineral density, both of which could be prevented by the arginase inhibitor ABH []. Lung cancer is a co-morbidity of COPD with a major role for arginase. Arginase expression is elevated in non-small cell lung cancer and drives proliferation by tumor cells and tumor associated fibroblasts, possibly via polyamine production or by lowering vasodilating NO, facilitating hypoxia that promotes cancer stem cell survival [71]. Arginase is also a marker of myeloid derived suppressor cells that are anti-inflammatory and repress cytotoxic T-cell responses [72]. In T-cell biology, arginase therefore promotes tolerance and arginase inhibition boosts anti-tumor T-cell activity [73•, 74, 75].