PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion.
PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion.
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DOI：
10.3389/fcvm.2021.633212
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发表时间：
2021
影响因子：
3.6
通讯作者：
Lucas AR
中科院分区：
文献类型：
--
作者：
Guo Q;Yaron JR;Wallen JW 3rd;Browder KF;Boyd R;Olson TL;Burgin M;Ulrich P;Aliskevich E;Schutz LN;Fromme P;Zhang L;Lucas AR
弥漫性肺泡出血(DAH)是系统性红斑狼疮(SLE)最严重的临床并发症之一。据报道，DAH的患病率在1%到5%之间，但尽管DAH被认为是一种罕见的并发症，但据报道有50%-80%的死亡率。目前还没有被证明有效的治疗DAH的方法，而且已经测试的治疗方法有显著的副作用。显然，有必要发现新的药物来改善DAH的结果。丝氨酸蛋白酶抑制剂，蛇毒，调节血栓形成和溶栓蛋白酶级联。我们正在研究一种粘瘤病毒衍生的免疫调节丝氨酸，SERP-1，作为一种治疗血管病变和肺出血的新型免疫调节药物。SERP-1已被证明在疱疹病毒诱导的动脉炎症(脉管炎)和肺出血模型中有效，并在临床试验中被证明对不稳定冠脉综合征和支架植入患者是安全的。在这里，我们研究了SERP-1，作为一种由CHO细胞表达的天然分泌蛋白和作为聚乙二醇化(PEGylated)变异体(SERP-1M5)，用于DAH的潜在治疗。给C57BL/6J(B6)小鼠腹腔注射泼尼松(Pristane)诱发DAH。小鼠在诱发DAH后给予100 ng/g体重的SERP-1作为天然55 kDa分泌型糖蛋白、SERP-1M5或生理盐水对照组。每天重复治疗14天(每组6只小鼠)。大体病理和HE染色显示，与生理盐水相比，SERP-1和SERP-1M5可显著减少Pristane诱导的DAH(SERP-1，p=0.2172；SERP-1M5，p=0.0252)。SERP-1M5和SERP-1治疗均可减少血管周围炎症，减少M1巨噬细胞(SERP-1，p=0.0350；SERP-1M5，P=0.0053)、含铁血黄素巨噬细胞(SERP-1，P=0.0370；SERP-1M5，P=0.0424)的侵袭和补体C5b/9染色。细胞外尿激酶型纤溶酶原激活物受体阳性(uPAR+)簇显著减少(SERP-1，P=0.0172；SERP-1M5，P=0.0025)。SERP-1M5组大鼠肺组织uPAR+肺泡数也明显增加(p=0.0091)。综上所述，SERP-1M5显著减少了SLE DAH模型的肺损伤和出血，提供了一种新的潜在的治疗方法。
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.
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