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α1-Antitrypsin: what it tells us about COPD
S60 Cigarette smoke induced oxidation of α-1 antitrypsin amplifies the pulmonary inflammatory response
  1. S Alam,
  2. Z Li,
  3. R Mahadeva
  1. University of Cambridge, Cambridge, UK


Alpha-1 antitrypsin (AT) is the major elastase inhibitor within the lung. Oxidation of critical methionine residues in AT (Ox-AT) has diminished ability to inhibit neutrophil elastase, which is thought to contribute to the pathogenesis of COPD. Ox-AT may also be pro-inflammatory. We investigated whether cigarette smoke would promote production of Ox-AT and an exaggerated inflammatory response. Adult female transgenic mice for human M-AT and wild type CBA mice (n=9 per group) were exposed to cigarette smoke (CS) from 1R3F research grade cigarettes for 5 days and killed 1 day later. Control mice were exposed to air. Ox-AT and inflammatory chemokines were assessed in BALF and lung homogenates (LH) by ELISA and Western blot. Ox-AT was not detected in control M-AT mice nor CS-CBA mice, but was significantly increased in BALF, 72.3 ng/ml (SEM±11.7), p=0.017 and LH, 1351.3 (±111.6) p=<0.001 of CS-M-AT mice. This was confirmed on western blot of SDS-PAGE using a monoclonal antibody to Ox-AT. There was a significant increase in BAL polymorphonuclear cells (1.53(104) (±0.02) vs 0.16 (104) (±0.04) p=0.022) and macrophages (16.36 (104) (±0.69) vs 10.19(104) (±1.94) p=0.008) in CS-M-AT mice compared with CS-CBA mice. There was significantly greater MCP-1 and KC in CS-M-AT vs CS-CBA; BALF, MCP-1 521.35 pg/ml (±46.7) vs 264.63 (±17.65), respectively; p=0.006, and KC 440.5 pg/ml (±53) vs 171.4 (±17), p=0.024. In LH, CS-M-AT MCP-1, 779.6 (±55) vs CS-CBA 368.8 (±30) (pg/ml) p=0.003, and CS-M-AT KC 466.1 (±67) vs 250.9 (±14), p=0.003. Similarly there was significantly increased NF-кB (p=0.015) and AP-1 (p=0.015) activity in CS-M-AT lungs compared with CS-CBA lungs. These findings demonstrate that oxidation of methionines in AT by oxidants released from cigarette smoke not only reduces the anti-elastase lung protection but converts AT into a pro-inflammatory stimulus. Ox-AT generated in the airway interacts directly with epithelial cells to release MCP-1 and IL-8, so enhancing lung inflammation. This mechanism could potentially contribute to the abnormal inflammatory response seen in COPD.

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