Increased Levels of Oxidized Methionine Residues in Bronchoalveolar Lavage Fluid Proteins from Patients with Idiopathic Pulmonary Fibrosis

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.

Section: Discussionmentioning

confidence: 99%

The oxidation induced by antimyeloperoxidase antibodies triggers fibrosis in microscopic polyangiitis

Guilpain¹,

Chéreau²,

Goulvestre³

et al. 2010

“…The results were compared to glutathione concentrations and redox balance in the epithelial lining fluid (ELF), in order to test the hypothesis that ROMs released from bronchoalveolar inflammatory cells (BA-cells) contribute to an impairment of the antioxidant capacity of the lung, thereby potentially aggravating oxidant injury. Oxidative stress was assessed by quantifying the methionine sulphoxide content of proteins contained in ELF [11,15,16].…”

Section: Ba-cells Obtained By Bronchoalveolar Lavage (Bal) Were Incubmentioning

confidence: 99%

Increased oxidation of extracellular glutathione by bronchoalveolar inflammatory cells in diffuse fibrosing alveolitis

Behr¹,

Degenkolb²,

Maier³

et al. 1995

An unbalanced oxidative stress is thought to be an important element in the pathogenesis of diffuse fibrosing alveolitis (DFA). The purpose of our study was to investigate the role of reactive oxygen metabolites (ROMs) released from cultured bronchoalveolar inflammatory cells (BA-cells) on glutathione oxidation. We studied bronchoalveolar lavage samples from 10 healthy controls and from 20 patients with diffuse fibrosing alveolitis (all were nonsmokers). BA-cells obtained by bronchoalveolar lavage (BAL) were incubated with 50 microM of reduced glutathione (GSH). Oxidation of GSH to glutathione disulphide (GSSG) by BA-cell derived oxidants was detected as a decline of GSH in the supernatants. Total glutathione (GSHtot = GSH + 2 GSSG) and GSSG in the epithelial lining fluid (ELF), and methionine sulphoxide (Met(O)) content of BAL proteins were determined. In diffuse fibrosing alveolitis the oxidative activity of BA-cells was enhanced, GSHtot and GSH were decreased, whereas the GSSG:GSH ratio was increased. The oxidative activity of BA-cells correlated positively with the GSSG:GSH ratio, but not with the methionine sulphoxide content. The methionine sulphoxide content was elevated in diffuse fibrosing alveolitis and inversely correlated with GSHtot. The methionine sulphoxide content also correlated positively with the percentage of BAL neutrophils. We conclude that BA-cell-derived reactive oxygen species are capable of oxidizing extracellular GSH in vitro. The positive correlation between the BA-cell oxidative activity in vitro and GSSG:GSH ratio in ELF suggests that a similar oxidative effect on extracellular GSH may also occur in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

“…This oxidation system produces hypochlorite and chlorinated amines, which are potent oxidants of Met. Significantly increased Met(O) values were found in IPF-NS patients but not in SARC-NS patients [34] when compared to a NS control. No difference in the Met(O) response was found between the NS and S control groups [35].…”

Section: Discussionmentioning

confidence: 64%

“…Recently, another approach has been reported to study oxidative stress in the lungs by measuring methionine sulphoxide (Met(O)) formation in BALF proteins [34,35]. The oxidation of methionine (Met) to Met(O) requires H 2 O 2 , chloride and MPO activity.…”

Section: Discussionmentioning

confidence: 99%

Oxidized BAL fluid proteins in patients with interstitial lung diseases

Lenz

Costabel²,

Maier³

1996

103

Oxygen-derived free radicals, released by phagocytic cells, have been postulated to contribute to lung tissue damage. We therefore investigated oxidative damage to proteins from bronchoalveolar lavage fluid (BALF) as an indicator of oxidative stress and to assess antioxidant defences in the lungs.We examined BAL fluids from patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF, nonsmokers (NS) and smokers (S)), sarcoidosis (SARC, nonsmokers), and asbestosis (ASB, ex-smokers (EXS)). The oxidation of BALF proteins is accompanied by the introduction of carbonyl groups into their amino acid side-chains and can be quantitated by labelling these groups with tritiated borohydride.The total lung content of oxidized proteins recovered by bronchoalveolar lavage (BAL) was 0.3±0.07 nmol carbonyl·mL -1 BALF (mean±SEM) in the NS control group (n=9) and tended to be increased, in the asymptomatic S group (n=8; 0.59± 0.14 nmol·mL -1 ). This parameter was significantly elevated both in IPF-NS (n=14; 0.