Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits afer heterotopic cardiac transplantation.

Abstract

We have related experimentally induced post-cardiac transplant coronary arteriopathy to increased elastolytic activity, IL-1 ␤ , fibronectin-mediated inflammatory and smooth muscle cell (SMC) migration, and SMC proliferation. Since our in vitro studies show that a serine elastase releases SMC mitogens and facilitates IL-1 ␤ induction of fibronectin, we hypothesized that administration in vivo of the specific serine elastase inhibitor, elafin, would decrease the post-cardiac transplant coronary arteriopathy. Cholesterol-fed rabbits underwent a heterotopic cardiac transplant without immunosuppression and received elafin (1.79 mg/kg per d continuous infusion after a 9 mg bolus, n ϭ 6) or vehicle ( n ϭ 6). 1 wk later, hearts were harvested for morphometric, immunohistochemical, and biochemical analyses. A Ͼ 70% decrease in the total number of coronary arteries with intimal thickening in elafin-treated compared to control donor hearts ( P Ͻ 0.002) was associated with reduced vascular elastolytic activity judged by fewer breaks in the internal elastic lamina ( P Ͻ 0.03), less accumulation of immunoreactive fibronectin ( P Ͻ 0.02), and reduced cell proliferation quantified by proliferating cell nuclear antigen ( P Ͻ 0.0001). Despite myocardial lymphocytic infiltration, wet weight of elafin-treated donor hearts was reduced by 50% compared to untreated controls ( P Ͻ 0.002) and associated with relative preservation of myocyte integrity, instead of extensive myocardial necrosis ( P Ͻ 0.004). This protective effect correlated with decreased myocardial elastolytic activity ( P Ͻ 0.0001) and inflammatory cell proliferation ( P Ͻ 0.0001) and with an elafin-inhibitable elastase in lymphocytes. Serine elastase activity thus appears an important therapeutic target for post-cardiac transplant coronary arteriopathy and myocardial necrosis induced by rejection. ( J. Clin. Invest. 1996. 97:2452-2468.)

Adenoviral Gene Delivery of Elafin and Secretory Leukocyte Protease Inhibitor Attenuates NF-κB-Dependent Inflammatory Responses of Human Endothelial Cells and Macrophages to Atherogenic Stimuli

“…It is noteworthy that both of these anti-inflammatory actions were associated with reduced activation of the transcription factor NF-B and concomitant increase in IB␣ protein. Our findings extend the observed potential of elafin augmentation in models of arterial wall inflammation, including vein graft degeneration (16) and transplant arteriosclerosis (17). They indicate that gene augmentation of both elafin and mSLPI may have therapeutic potential in the treatment of atherosclerosis.…”

Neutrophil Elastase Is Produced by Pulmonary Artery Smooth Muscle Cells and Is Linked to Neointimal Lesions

“…28 The FLAG-elafin was conjugated to a FLAG affinity column using a FLAG-tagged protein immunopreciptation kit (Sigma). Protein extracts were prepared as described above for the elastase activity assays, using lungs of S100A4 mice 7 days after inoculation with M1-MHV-68.…”

“…opathy after transplantation, 28,51 vein graft atherosclerosis 52 and fibrosis following viral myocarditis, 53,54 or pulmonary hypertension induced by hypoxia 12,14 or monocrotaline. 13,15 In five of these models, 28,50,52,54 elafin was used as the elastase inhibitor, given as an infusion, 28 by gene therapy 50,52 or in an overexpressing transgenic mouse.…”

“…13,15 In five of these models, 28,50,52,54 elafin was used as the elastase inhibitor, given as an infusion, 28 by gene therapy 50,52 or in an overexpressing transgenic mouse. 14,49,54 Elafin is a small, 9-kDa protein, first described in association with inflammatory lesions in the airways 55 and with psoriasis in skin.…”

Granzyme Activity in the Inflamed Lung Is Not Controlled by Endogenous Serine Proteinase Inhibitors

“…Some have reported that ␣ 1 -antitrypsin inhibits granzyme B (17), while we (C.E.H., unpublished observations) and others (P. Bird, personal communication) have not observed such inhibition. Since elafin suppresses by 75% the degradation of insoluble elastin by purified peripheral blood T cells (18), and granzyme A is elastolytic (19), it has been suggested that elafin inhibits granzyme A (18). To our knowledge, there are no data available on granzyme inhibition by SLPI.…”