Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

Abstract

Chronic hypoxia causes pulmonary hypertension with smooth muscle cell proliferation and matrix deposition in the wall of the pulmonary arterioles. We demonstrate here that hypoxia also induces a pronounced inflammation in the lung before the structural changes of the vessel wall. The proinflammatory action of hypoxia is mediated by the induction of distinct cytokines and chemokines and is independent of tumor necrosis factor-␣ signaling. We have previously proposed a crucial role for heme oxygenase-1 (HO-1) in protecting cardiomyocytes from hypoxic stress, and potent anti-inflammatory properties of HO-1 have been reported in models of tissue injury. We thus established transgenic mice that constitutively express HO-1 in the lung and exposed them to chronic hypoxia. HO-1 transgenic mice were protected from the development of both pulmonary inflammation as well as hypertension and vessel wall hypertrophy induced by hypoxia. Significantly, the hypoxic induction of proinflammatory cytokines and chemokines was suppressed in HO-1 transgenic mice. Our findings suggest an important protective function of enzymatic products of HO-1 activity as inhibitors of hypoxia-induced vasoconstrictive and proinflammatory pathways.A cute hypoxia in the lung causes arteriolar vasoconstriction whereas prolonged hypoxia promotes proliferation and migration of vascular smooth muscle cells (VSMC) and extracellular matrix deposition in the arterial wall, a process known as vascular remodeling (1). These abnormalities are characteristic of pulmonary hypertension (2). Several clinical conditions characterized by lung inflammation have been linked to the development of chronic pulmonary hypertension (3). Interestingly, perivascular inflammatory cell infiltration as well as increased serum levels of proinflammatory cytokines, such as IL-1␤ and IL-6, have been reported in clinical cases of primary pulmonary hypertension (4, 5). However, little attention has been given up to now to the role of pulmonary inflammation in the pathogenesis of pulmonary hypertension induced by hypoxia.Heme oxygenase (HO; EC 1.14.99.3) catalyzes the oxidation of heme to carbon monoxide (CO) and biliverdin, which is then converted to bilirubin by biliverdin reductase. Three isoforms of HO have been identified: the inducible HO-1 and the constitutively expressed HO-2 and HO-3 (6, 7). Our previous in vitro data suggest that CO released by HO-1 confers protection against vasoconstriction and vascular remodeling induced by hypoxia (8 -10). More recently, Soares et al. have suggested antiinflammatory properties of HO-1 in a cardiac transplantation model, although the molecular mechanisms have not been fully elucidated (11). Our recent in vivo data using an HO-1 null mouse model suggest that HO-1 plays a central role in protecting the right ventricle from hypoxic pulmonary pressure-induced injury (12).In the present study, we established transgenic mice that overexpress HO-1 in the lung and exposed them to hypoxia to investigate the effects of HO-1 activity on the developmen...

Heme Oxygenase-2 Is a Critical Determinant for Execution of an Acute Inflammatory and Reparative Response

“…Sustained increases in their levels have been associated with persistent inflammation, neovascularization, and decreased re-epithelialization and tissue repair. 44 -47 The fact that these same chemokines are subjected to down-regulation by either HO-1 induction or supplementation of CO or biliverdin, 21,43,48,49 further underscores the notion that the absence of considerable HO activity promoted the uncontrolled massive production of proinflammatory signals and, consequently, chronic inflammation and neovascularization. This is strongly supported by the demonstration that biliverdin administration rescued the impaired inflammatory and reparative response of the HO-2-null mice; it accelerated wound repair, promoted resolution, and attenuated neovascularization.…”

“…More importantly, these inflammatory cells showed a weak HO-1 immunoreactivity. To the extent that the HO catalytic products, CO and biliverdin, are stop signals to control leukocyte migration and activation by attenuating adhesion molecule expression 8,17 and cytokine and chemokine induction, 20,22,[41][42][43] the lack of sufficient HO-1 levels in HO-2-null mice may increase migration, lower the threshold of leukocyte activation (ie, O 2 Ϫ generation) and contribute to leukocyte-mediated tissue injury. This notion is substantiated by results obtained with zymosan A-induced peritonitis in HO-2-null mice that demonstrated pronounced increases in leukocyte influx, NADPH oxidase activity, and KC levels, all associated with impaired induction of PMNs and macrophage HO-1.…”

Influence of heme oxygenase 1 modulation on the progression of murine collagen‐induced arthritis

“…HO-1 overexpression has shown antiinflammatory or immunomodulatory effects in models of acute disease (10,16,36,(45)(46)(47). Less is known about the possible role of this enzyme in chronic inflammatory diseases, which involve complex interactions between different cell populations and a wide range of mediators.…”

Hypoxia and chronic lung disease

“…The main hypotheses to explain HAPE lie on excessive vasoconstriction, excessive inflammation due to hypoxia, or downregulation of alveolar cell ion pumps that move sodium and fluid from alveoli into the blood stream [34]. As mice exposed to chronic hypoxia develop lung inflammation [35], it is conceivable that acute hypoxia may trigger acute lung inflammation. However, acute inflammation and HPV may not coexist, as inflammation caused by lipopolysaccharide prevents HPV (Fig.…”