Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline.

Abstract

Chronic pulmonary hypertension is associated with significant vascular remodeling. We demonstrated recently in the monocrotaline (MCT) and chronic hypoxia rat models of pulmonary hypertension that treatment with platelet-activating factor (PAF) antagonists inhibited the development of chronic pulmonary hypertension. PAF and other lipid mediators interact with interleukin-1. We postulated that chronic treatment with a recombinant human interleukin-1 receptor antagonist (IL-1ra) would inhibit development of chronic pulmonary hypertension in animal models. Rats were either injected with (60 mg/kg) MCT or exposed to a stimulated high altitude of 16,000 feet; half of the animals were treated with twice-daily injections (2 mg/kg) of IL-1ra. At 3 wk after MCT injection or 3 wk of hypoxic exposure, pulmonary artery pressure and right heart ventricle weight/(left ventricle and septum weight), RV/(LV + S), were measured. IL-1ra treatment reduced pulmonary hypertension and right heart hypertrophy in the MCT model, but not in the chronic hypoxia model. Measurement of lung homogenate IL-1 alpha by radioimmunoassay showed elevated levels in the MCT-treated rats throughout the 3-wk observation period. IL-1ra treatment reduced the levels of IL-1 alpha in lung tissue in most of the MCT-treated rats. MCT treatment was also associated with an increase in lung mRNA for IL-1 alpha, IL-1 beta, and IL-1ra. Immunohistology, using an antibody against rat IL-1 alpha, revealed staining of alveolar structures and of vascular and bronchial smooth muscle. In situ hybridization using a human IL-1 alpha cDNA probe demonstrated increased expression of the IL-1 alpha gene in the lung cells after endotoxin or MCT treatment. Northern blot analysis demonstrated low-level expression of IL-1 alpha mRNA in extracts of normal rat lung and increased expression after endotoxin or MCT treatment. We conclude that chronic treatment with human IL-1ra inhibited the development of pulmonary hypertension in the inflammatory (MCT) model, but not in the chronically hypoxic rats. This result indicates that IL-1 participates in the pathogenesis of some forms of pulmonary hypertension.

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

“…These cytokines were also reported to promote proliferation and migration of VSMC in vitro (18,19), and disruption of the CCR2 chemokine receptor gene decreased vascular remodeling in a model of atherosclerosis in vivo (24). Moreover, it was demonstrated that administration of an IL-1 receptor antagonist or anti-MCP-1 antibody protected against monocrotaline-induced pulmonary hypertension (25,26). Together with our data of pronounced cytokine and chemokine induction in hypoxic pulmonary hypertension, these findings suggest a crucial role for proinflammatory cytokines and chemokines in the development of pulmonary vascular remodeling.…”

Sterile inflammation and pregnancy complications: a review

“…An important role of IL-1 as a contributor to hypertension has been proposed (Voelkel et al 1994, Zou et al 2001, Krishnan et al 2014. Additionally, IL-1 is known to exacerbate inflammation in placenta (Baergen et al 1994, Nadeau-Vallee et al 2015b, the key organ in PE.…”

Update on pulmonary hypertension complicating chronic obstructive pulmonary disease

“…22 Monocrotaline has a marked predilection for pulmonary vascular endothelium and leads to the development of PH with marked inflammatory infiltration of the vessels. 23 This model suggests the role of toxin-mediated pulmonary vascular inflammation in PH development. Inflammatory cytokines such as interleukin-6 (IL-6), C-reactive protein, and tumor necrosis factor-α are markers of elevated PAP in COPD.…”