The oxidation induced by antimyeloperoxidase antibodies triggers fibrosis in microscopic polyangiitis

Abstract

Lung fibrosis is considered a severe manifestation of microscopic polyangiitis (MPA). Antimyeloperoxidase (anti-MPO) antibodies in MPA patients' sera can activate MPO and lead to the production of reactive oxygen species (ROS). While high levels of ROS are cytotoxic, low levels can induce fibroblast proliferation. Therefore, we hypothesised that the oxidative stress induced by anti-MPO antibodies could contribute to lung fibrosis.24 MPA patients (45 sera) were enrolled in the study, including nine patients (22 sera) with lung fibrosis. Serum advanced oxidation protein products (AOPP), MPO-induced hypochlorous acid (HOCl) and serum-induced fibroblast proliferation were assayed.AOPP levels, MPO-induced HOCl production and serum-induced fibroblast proliferation were higher in patients than in healthy controls (p,0.0001, p50.0001 and p50.0005, respectively). Increased HOCl production was associated with active disease (p50.002). Serum AOPP levels and serum-induced fibroblast proliferation were higher in patients with active MPA and lung fibrosis (p,0.0001). A significant linear relationship between fibroblast proliferation, AOPP levels and HOCl production was observed only in patients with lung fibrosis.Oxidative stress, in particular the production of HOCl through the interaction of MPO with anti-MPO antibodies, could trigger the fibrotic process observed in MPA.

Systemic Vasculitis During the Course of Systemic Sclerosis

“…47 Such a manifestation has been attributed to recurrent alveolar hemorrhage, but also to an accelerated fibrotic process related to increased oxidative stress mediated by anti-MPO antibodies. 17 Therefore, interstitial lung disease can also be a manifestation of anti-MPO-associated vasculitis rather than a component of SSc. AASV was diagnosed a mean 8 years after the diagnosis of SSc.…”

Increased incidence of autoimmune markers in patients with combined pulmonary fibrosis and emphysema

“…Nevertheless, interest in the role of autoimmunity in the pathophysiology of both IPF and COPD was revived by recent studies reporting highly activated and proliferative CD4+ cells [11] and global numerical and functional impairment of T regulatory cells [12], as well as presence of circulating auto-antibodies against nuclear and cytoplasmic antigens in both IPF and COPD patients [13,14]. Moreover, a close linkage between pulmonary fibrosis and microscopic polyangiitis (MPA), a type of systemic necrotizing small vasculitis characterized by both pulmonary and renal involvement and associated with circulating antineutrophil cytoplasm antibodies (ANCAs) against myeloperoxidase (MPO), has been recently identified in both clinical [15] and experimental setting [16]. The latter implies that an ongoing autoimmune process through recognition of self-antigens may take place in a subgroup of patients initially presented with a diagnosis of IPF.…”

Combined pulmonary fibrosis and emphysema associated with microscopic polyangiitis

“…Increased circulating levels of MPO on activated neutrophils for prolonged periods of time, especially in heavy smokers, may lead to loss of immune tolerance and acceleration of autoimmunity phenomena, including production of MPO-ANCA. The latter may promote degranulation of reactive oxygen species located within the neutrophilic cytoplasmic domain, resulting in an uncontrolled oxidative burst within the pulmonary interstitium that could promote fibroblast proliferation as well as alveolar epithelial and endothelial cell apoptosis, leading to fibrosis and emphysema development [9].…”