Abstract
Diffuse alveolar hemorrhage (DAH) is a fatal complication in patients with lupus. DAH can be induced in B6 mice by an intraperitoneal injection of pristane. Since human alpha-1-antitrypsin (hAAT) is an anti-inflammatory and immuno-regulatory protein, we investigated the protective effect of hAAT against pristane-induced DAH in B6 mice and hAAT transgenic (hAAT-Tg) mice. We first showed that hAAT Tg expression lowers TNF-α production in B cells, as well as CD4+ T cells in untreated mice. Conversely, the frequency of regulatory CD4+CD25+ and CD4+CD25-IL-10+ cells was significantly higher in hAAT-Tg than in B6 mice. This confirmed the anti-inflammatory effect of hAAT that was observed even at steady state. One week after a pristane injection, the frequency of peritoneal Ly6Chi inflammatory monocytes and neutrophils in hAAT-Tg mice was significantly lower than that in B6 mice. Importantly, pristane-induced DAH was completely prevented in hAAT-Tg mice and this was associated with a modulation of anti- to pro-inflammatory myeloid cell ratio/balance. We also showed that treatment with hAAT decreased the severity of DAH in B6 mice. These results showed for the first time that hAAT has a therapeutic potential for the treatment of DAH.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by the overexpression of autoantibodies causing multiple organ damage due to loss of tolerance to self-antigens [1]
We have shown that Human alpha-1-antitrypsin (hAAT) inhibits the activation of murine bone marrow derived dendritic cells (BMDCs) by lipopolysaccharides (LPS) or CpG, a TLR4 and TLR9 agonist, respectively, and their secretion of cytokines such as TNF-α, IL-6, IL-12, IL-1β, and IFN-I [48,49]
Splenocytes from hAAT transgenic (hAAT-Tg) Mice Are Less Susceptible to Activation
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by the overexpression of autoantibodies causing multiple organ damage due to loss of tolerance to self-antigens [1]. Lung disease occurs in half of SLE patients [2], in which diffuse alveolar hemorrhage (DAH) is a rare, but serious, complication of SLE [3,4]. DAH is characterized by capillaritis, hemorrhage, and interstitial infiltration by mononuclear and polynuclear leukocytes, alveolar necrosis, and deposits of hemosiderin macrophages [7,9,10]. Current treatments for DAH include steroids alone or in combination with immunosuppressive drugs, plasmapheresis, and mechanical ventilation [3,11]. DAH can often recur and is usually fatal [6,12]. There is an unmet need for a safe and effective treatment of DAH
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