we have not been able to detect DNA methylation aberrations in specific loci in

By regulating the availability of L arginine for NOS, arginase induction may have an important impact on the induction of AHR. It is interesting Dapagliflozin SGLT inhibitor to note that IL 13 induced AHR occurs in a time frame that paral lels arginase induction, suggesting that the ability of IL 13 to promote AHR may be directly dependent on arginase induction. This may be particularly impor tant because IL 13 has been recently shown to be a major effector cytokine in asthma pathogenesis, Notably, the mechanism by which IL 13 induces AHR has been unclear,our results draw attention to the ability of IL 13 to regulate arginase as a possible mechanism of AHR. In addition to affecting AHR, we propose that arginase downstream products are also involved in asthma patho genesis. Indeed, we have found elevated levels of putrescine in the asthmatic murine lung, and elevated levels of polyamines have been reported in the serum of patients with asthma, corroborating the pro duction of biologically active mediators downstream from arginase. Interestingly, polyamines have con tractile activity on smooth Gene expression muscle, possibly implicating them in asthma associated AHR. Poly amines are present in multiple cell types in the lung, The ability of polyamines to affect multiple processes, including cell survival, cell proliferation, and mucus production, indi cates that they may have numerous functions in sever al cell types present in the asthmatic lung. Work from several laboratories has led to the notion that macrophage derived arginase has a role in the recovery of host tissues from inflammation, This effect is not only mediated by competing with NOS for L arginine as a substrate, but also by generating L ornithine for synthesis of proline, This may be particularly SMER 3 important in inflammatory sites charac terized by tissue remodelingrepair because proline often becomes a rate,limiting substrate for collagen synthesis, Under these conditions, it is believed that extracellu lar L ornithine and proline, secreted from arginase expressing cells are transported into fibroblasts, where they subsequently become incorporated into collagen, In summary, we have described a pathway not previously exam ined in the context of allergic airway inflammation. Our results challenge the conventional view that argi nine is primarily metabolized by NOS in asthmatic responses,rather, we propose that significant metabo lism occurs by arginase, and that this process has important ramifications on the manifestations of dis ease. As such, this new pathway may represent an important therapeutic intervention strategy for the treatment of allergic lung disease. Janus kinase 2 is an intracellular tyrosine kinase that associates with the cytoplasmic do mains of multiple cytokine receptors.