Effects of inducible nitric oxide synthase inhibition in bronchial vascular remodeling-induced by chronic allergic pulmonary inflammation

Abstract

Vascular remodeling is an important feature in asthma pathophysiology. Although investigations suggested that nitric oxide (NO) is involved in lung remodeling, little evidence established the role of inducible NO synthase (iNOS) isoform in bronchial vascular remodeling. The authors investigated if iNOS contribute to bronchial vascular remodeling induced by chronic allergic pulmonary inflammation. Guinea pigs were submitted to ovalbumin exposures with increasing doses (1∼5 mg/mL) for 4 weeks. Animals received 1400W (iNOS-specific inhibitor) treatment for 4 days beginning at 7th inhalation. Seventy-two hours after the 7th inhalation, animals were anesthetized, mechanical ventilated, exhaled NO was collected, and lungs were removed and submitted to picrosirius and resorcin-fuchsin stains and to immunohistochemistry for matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and transforming growth factor-β (TGF-β). Collagen and elastic fiber deposition as well as MMP-9, TIMP-1, and TGF-β expression were increase in bronchial vascular wall in ovalbumin-exposed animals. The iNOS inhibition reduced all parameters studied. In this model, iNOS inhibition reduced the bronchial vascular extracellular remodeling, particularly controlling the collagen and elastic fibers deposition in pulmonary vessels. This effect can be associated to a reduction on TGF-β and on metalloproteinase-9/TIMP-1 vascular expression. It reveals new therapeutic strategies and some possible mechanism related to specific iNOS inhibition to control vascular remodeling.

Transforming growth factor‐beta 1 pathways in inflammatory airway diseases

“…In lower airways, there are several mechanisms participating in airway inflammation, especially via cytokines such as TGF-b1, IL-10, IL-1b 1, PGs (e.g., PGE2), LTs, and NO, which are interacting with each other (46). In vitro experiments indicated that recombinant IL-10 up-regulated TGFb1 expression in alveolar macrophages, and in contrast, it down-regulated PGE2 production in both lung fibroblasts and macrophages (47).…”

Safranal of Crocus sativus L. Inhibits Inducible Nitric Oxide Synthase and Attenuates Asthma in a Mouse Model of Asthma

“…NO may thus react with the superoxide ions and hence leads to the generation of a more toxic molecule, peroxynitrite. Peroxynitrite ion leads to protein degradation, mitochondrial dysfunction, and epithelial cell damage (Mabalirajan and Ghosh, 2013), which is a well documented phenomenon during asthma (Prado et al, 2011). During asthma, increased expression of iNOS has been shown unequivocally (Riku et al, 2005).…”

Metalloproteinases as modulators of allergic asthma: therapeutic perspectives

“…Percent collagen and elastic fibers were significantly increased in ovalbuminchallenged guinea pigs as compared to saline controls, but treatment with 1400W, a specific inhibitor of inducible nitric oxide synthase, significantly reduced this response as well as reduced immunostaining of MMP-9, TIMP-1, and TGFβ1 in airway vascular wall. 94 In human allergic asthma, MMP-9 activity and secretion in BAL fluid were significantly increased in asthma patients with mucus hypersecretion and in subjects with severe asthma as compared to mild/ moderate asthma subjects and healthy controls. 95 Also, Pham et al demonstrated that MMP-9 protein and MMP-9/TIMP-1 ratios were significantly elevated in the BAL of subjects with nocturnal asthma as compared to asthmatic subjects without nocturnal symptoms.…”