Heme oxygenase attenuates allergen-induced airway inflammation and hyperreactivity in guinea pigs

Abstract

Heme oxygenase (HO), the heme-degrading enzyme, has shown anti-inflammatory effects in several models of pulmonary diseases. HO is induced in airways during asthma; however, its functional role is unclear. Therefore, we evaluated the role of HO on airway inflammation [evaluated by bronchoalveolar lavage (BAL) cellularity and BAL levels of eotaxin, PGE(2), and proteins], mucus secretion (evaluated by analysis of MUC5AC gene expression and periodic acid-Schiff staining), oxidative stress (evaluated by quantification of 4-hydroxynonenal adducts and carbonylated protein levels in lung homogenates), and airway responsiveness to histamine in ovalbumin (OVA)-sensitized and multiple aerosol OVA or saline-challenged guinea pigs (6 challenges, once daily, OVA group and control group, respectively). Airway inflammation, mucus secretion, oxidative stress, and responsiveness were significantly increased in the OVA group compared with the control group. HO upregulation by repeated administrations of hemin (50 mg/kg i.p.) significantly decreased airway responsiveness in control animals and airway inflammation, mucus secretion, oxidative stress, and responsiveness in OVA animals. These effects were reversed by the concomitant administration of the HO inhibitor tin protoporphyrin-IX (50 micromol/kg i.p.). Repeated administrations of tin protoporphyrin-IX alone significantly increased airway responsiveness in control animals but did not modify airway inflammation, mucus secretion, oxidative stress, and responsiveness in OVA animals. These results suggest that upregulation of the HO pathway has a significant protective effect against airway inflammation, mucus hypersecretion, oxidative stress, and hyperresponsiveness in a model of allergic asthma in guinea pigs.

Dimethylfumarate inhibits CXCL10viahaem oxygenase-1 in airway smooth muscle

“…In this study, we were interested in whether DMF-mediated up-regulation of HO-1 is also involved in DMF's anti-inflammatory effects. A beneficial anti-inflammatory effect of HO-1 has been suggested in other allergic diseases and may indicate an overall protective anti-inflammatory effect of DMF [21,22]. Similar to our results, pyrrolidine dithiocarbamate induced HO-1 expression, which reduced eosinophil and T-cell counts in bronchoalveolar lavage fluid, as well as airway hyperresponsiveness in a mouse model of allergic airway disease [23].…”

“…The observed reduced eosinophil activity may be related to our finding that DMF reduced the secretion of eotaxin and RANTES by blocking histone 3 phosphorylation [19]. Further beneficial effects of increasing HO-1 expression in the inflamed lung may be related to reduced airway inflammation, mucus secretion, oxidative stress and airway hyper-responsiveness, which were shown in an asthma model of ovalbumin-sensitised guinea pigs [22]. In our study, DMF induced HO-1 in the presence of TNF-a and this effect was abrogated in ASMCs that had been treated with HO-1 siRNA.…”

Overexpression of HO-1 Protects against TNF-α-Mediated Airway Inflammation by Down-Regulation of TNFR1-Dependent Oxidative Stress

“…Moreover, HO-1 possesses antioxidant and anti-inflammatory properties. 25 Overexpression of HO-1 has been shown to decrease airway inflammation and airway responsiveness to histamine in ovalbumin-sensitized guinea pigs, 29 suggesting that HO-1 plays a critical role in protecting the host during airway inflammation. However, the molecular mechanisms underlying overexpression of HO-1-inhibited inflammatory response in HTSMCs remain unclear.…”

Lipoteichoic Acid Induces HO-1 Expression via the TLR2/MyD88/c-Src/NADPH Oxidase Pathway and Nrf2 in Human Tracheal Smooth Muscle Cells

“…Recently, HO-1 has been reported to be induced in airways of patients with asthma and chronic obstructive pulmonary disease (17). Moreover, overexpression of HO-1 has been shown to decrease airway inflammation, mucus secretion, and airway responsiveness to histamine in OVA-sensitized guinea pigs (36), suggesting that HO-1 plays a critical role in protecting the host during airway inflammation. Thus, the induction of HO-1 expression by various stress stimuli, such as LPS and oxidants, is thought to be an adaptive mechanism that protects the cells from oxidative injury (13).…”