Abstract
Diffuse alveolar hemorrhage (DAH) is one of the most serious clinical complications of systemic lupus erythematosus (SLE). The prevalence of DAH is reported to range from 1 to 5%, but while DAH is considered a rare complication there is a reported 50–80% mortality. There is at present no proven effective treatment for DAH and the therapeutics that have been tested have significant side effects. There is a clear necessity to discover new drugs to improve outcomes in DAH. Serine protease inhibitors, serpins, regulate thrombotic and thrombolytic protease cascades. We are investigating a Myxomavirus derived immune modulating serpin, Serp-1, as a new class of immune modulating therapeutics for vasculopathy and lung hemorrhage. Serp-1 has proven efficacy in models of herpes virus-induced arterial inflammation (vasculitis) and lung hemorrhage and has also proved safe in a clinical trial in patients with unstable coronary syndromes and stent implant. Here, we examine Serp-1, both as a native secreted protein expressed by CHO cells and as a polyethylene glycol modified (PEGylated) variant (Serp-1m5), for potential therapy in DAH. DAH was induced by intraperitoneal (IP) injection of pristane in C57BL/6J (B6) mice. Mice were treated with 100 ng/g bodyweight of either Serp-1 as native 55 kDa secreted glycoprotein, or as Serp-1m5, or saline controls after inducing DAH. Treatments were repeated daily for 14 days (6 mice/group). Serp-1 partially and Serp-1m5 significantly reduced pristane-induced DAH when compared with saline as assessed by gross pathology and H&E staining (Serp-1, p = 0.2172; Serp-1m5, p = 0.0252). Both Serp-1m5 and Serp-1 treatment reduced perivascular inflammation and reduced M1 macrophage (Serp-1, p = 0.0350; Serp-1m5, p = 0.0053), hemosiderin-laden macrophage (Serp-1, p = 0.0370; Serp-1m5, p = 0.0424) invasion, and complement C5b/9 staining. Extracellular urokinase-type plasminogen activator receptor positive (uPAR+) clusters were significantly reduced (Serp-1, p = 0.0172; Serp-1m5, p = 0.0025). Serp-1m5 also increased intact uPAR+ alveoli in the lung (p = 0.0091). In conclusion, Serp-1m5 significantly reduces lung damage and hemorrhage in a pristane model of SLE DAH, providing a new potential therapeutic approach.
Highlights
Systemic lupus erythematosus (SLE), or lupus, is an autoimmune disease characterized by immune cell hyperactivity, production of antibodies against self-antigens, such as double-stranded DNA, histones, and ribonucleoprotein (RNP)
Trichrome staining revealed a trend toward a reduction in collagen or fibrous tissue staining around areas of excess hemorrhage, with both Serp-1m5 and Serp-1 treatments (Figure 4)
The pathogenesis of diffuse alveolar hemorrhage (DAH) is reported to be caused by defects in macrophage phagocytic function and reduction in the removal of apoptotic cells
Summary
Systemic lupus erythematosus (SLE), or lupus, is an autoimmune disease characterized by immune cell hyperactivity, production of antibodies against self-antigens, such as double-stranded (ds) DNA, histones, and ribonucleoprotein (RNP). The etiology of SLE is only partially defined and has been linked to abnormal genetic, hormonal, and environmental responses [1,2,3,4] The incidence of this disease is 20–70 per 100,000 people, and the incidence in women is 6–10 times that of men. The current treatment options for DAH include steroids, cyclophosphamide, rituximab, methotrexate, azathioprine, respiratory support, and among others. The efficacy of these treatments is limited and there are many significant side effects, that include hypertension, diabetes, osteoporosis, adrenal suppression, infertility, pulmonary fibrosis, hepatotoxicity, and risk for future malignancies. There is an urgent, unmet need for new drugs to improve treatment for DAH
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