Inhibition or knock out of Inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury

Abstract

Background: In the present study, by comparing the responses in wild-type mice (WT) and mice lacking (KO) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the role played by iNOS in the development of on the lung injury caused by bleomycin administration. When compared to bleomycin-treated iNOSWT mice, iNOSKO mice, which had received bleomycin, exhibited a reduced degree of the (i) lost of body weight, (ii) mortality rate, (iii) infiltration of the lung with polymorphonuclear neutrophils (MPO activity), (iv) edema formation, (v) histological evidence of lung injury, (vi) lung collagen deposition and (vii) lung Transforming Growth Factor beta1 (TGF-β1) expression.

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

“…In agreement with previous studies, we observed increased expression and activity of iNOS in lung tissue with both experimental and clinical PF (11,62). Nos2 -/-mice displayed lower levels of fibrosis than WT mice after bleomycin challenge ( Figure 5), in agreement with published findings (11,15); this also suggested that pharmacological inhibition of iNOS has therapeutic benefit in PF (14,15). Our finding that combined inhibition of CB 1 R and iNOS results in greater antifibrotic efficacy than equivalent inhibition of CB 1 R alone confirms this notion, and it also indicates that iNOS signals through targets not engaged by CB 1 R.…”

“…Pharmacological inhibition or genetic deletion of Cnr1 was reported to mitigate PF and improve survival in mice following thoracic irradiation (26), but a similar role of CB 1 R in IPF and BL-PF has not yet been investigated. On the other hand, the involvement of iNOS in human IPF and in BL-PF was suggested in several prior studies (11,15). In view of the observed activation of both the endocannabinoid/CB 1 R system and iNOS in BL-PF, we explored the effect of gene deletion of Cnr1 and Nos2 on fibrosis development in this model.…”

“…Furthermore, iNOS inhibitors have antifibrotic activity in animal models of PF (14,15), making iNOS a viable therapeutic target for PF.…”

Peroxisome Proliferator-activated Receptor γ Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression

“…The thiazolidinedione compounds and certain prostaglan- dins have been used to demonstrate that activation of PPAR␥ inhibits collagen synthesis (18) and fibrosis in lung (14,15,19,57), kidney (8,9,58), liver (10,11,33,36,59), cardiac fibroblasts (60), and skin (61). The issue of endogenous ligand for PPAR␥ in cells has been controversial.…”

“…Synthetic antagonists of PPAR␥ are also available to inhibit PPAR␥ activity (5-7). Activation of PPAR␥ by agonists attenuates fibrosis in several organs, including kidneys (8,9), liver (10,11), heart (13), and lungs (14,15), and arteries in atherosclerosis (12) . Several studies suggest that PPAR␥ inhibits extracellular matrix synthesis, including collagen (16 -18).…”