Interleukin‐1 Receptor Antagonist Inhibits Pulmonary Hypertension Induced by Inflammation a

Structural alterations of the lung vessels can occur in each part of the vascular tree including the lung capillaries. In addition to the well-established forms of angitis, there is increasing evidence that inflammatory mechanisms defined by cell-cell interactions and mediator release are part of chronic pulmonary vascular disorders associated with the development of pulmonary hypertension. Patients with chronic obstructive pulmonary diseases and patients with a smoking history demonstrate muscularization of their pulmonary small arteries4 and intravascular cell aggregates consisting of neutrophils, monocytes, and platelets-aided perhaps by alveolar macrophages-these cells could provide the cytokines and growth factors involved in the structural alterations characteristic for chronic pulmonary hypertensive states.' In this study we examine the hypothesis that interleukin-I ( IL-I ) play5 an important part in the development of chronic pulmonary hypertension and in the vascular remodeling process that accounts for the structural alterations of hypertensive lung vessels. We take the view that the 17.000 Dalton polypeptide. which is synthesized in two major species, IL-cy and IL-/3 acts on the lung vessels either directly or in Combination with lipid mediators. Our approach is to examine in two accepted experimental models of chronic pulmonary hypertension'.3 whether treatment with the interleukin-I receptor antagonist (IL-lra)"~' prevents development of pulmonary hypertension. The monocrotaline (MCT) rat model8 represents the paradigm of inflammatory pulmonary hypertension, whereas the model of chronic hypoxia exposure represents a / w r s c noninflammatory model of hypertension.y Our rationale for such a pharmacological approach stems from the Combination of several pertinent facts regarding the action of interleukin-I. This cytokine acts as a procoagulant. stimulates the production of collagen in fibroblasts.'" i t is produced by endothelial cells iti uitro," and it is mitogenic for fibroblasts and vascular smooth-muscle cells."-'4 Moreover, the actions of ILI and of platelet activating factor (PAF) and of eicosanoids are apparently intertwined such that the inhibition of the action of PAF or of eicosanoid synthesis may result in the inhibition of synthesis of action of IL-l . '5 ,16 Finally, i t has been shown that mono-