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P185 Pulmonary infection in PiZZ antitrypsin individuals is associated with increased oxidative and nitrosative stress
  1. S Alam,
  2. J Parmar,
  3. K Santhanakrishnan,
  4. R Mahadeva
  1. University of Cambridge, Cambridge, UK

Abstract

Severe deficiency of the major anti-elastase α1-antitrypsin (AT) due to the Z (Glu342Lys) variant is associated with early-onset emphysema which can require lung transplantation. AT is mainly produced by the liver and a lesser proportion (around 10%) is produced in the lung. Therefore individuals with Z-AT post-lung transplantation remain severely deficient in AT. We studied patients with and without AT deficiency with infection (post lung transplantation) to examine the relationship between deficiency of AT and oxidative/nitrosative stress.

BALF was obtained at scheduled surveillance, and when clinically indicated to assess for infection, rejection and airway injury. 25 patients post-transplant were evaluated; 12/26 samples from 12 Z-AT patients had infective tracheobronchitis, and 7/29 samples from 13 M(normal)-AT had infective tracheobronchitis. The level of oxidative stress (F2-Isoprostane), TNF-α, IL-1β, IFN-γ was quantified using respective ELISA kits and for total glutathione (GSH) and oxidised GSH (GSSG) using OxiSelect™ Total Glutathione (GSSG/GSH) Assay Kit and nitrosative stress using Griess reagent.

BALF of Z-AT patients with infection had increased oxidative stress compared to infected M-AT patients; F2-Isoprostane, 773SEM ± 79.5 pg/ml vs. 425.8 ± 53.2, P < 0.001 respectively, oxidised glutathione (0.112 ± 0.1μM/ml vs. 0.155 ± 0.1, P = 0.027). However, total glutathione was unchanged (0.885 ± 13 μM/ml vs. 1.17 ± 0.141, P = 0.117). There was increased nitrosative stress in Z-AT vs. M-AT patients (nitrite release as a measure of nitric oxide (NO) production (261 ± 47 pg/ml vs. 117 ± 41.2, P < 0.001), and increased levels of TNF-α (91 ± 16.3 pg/ml vs. 59 ± 10.5, P = 0.002), IL-1β (121.2 ± 17.4 pg/ml vs. 69.6 ± 5.8, P = 0.047) and IFN-γ (481.3 ± 74.8 pg/ml vs. 201.2 ± 28.5, P = 0.025). Infected Z-AT BALF had increased free HLE compared to infected M-AT patients (167 ± 16 ng/ml vs. 42.7 ± 16, P < 0.001).

In conclusion, Z-AT lungs had increased oxidative and nitrosative stress, and furthermore had increased levels of cytokines that are associated with induction of the inducible NO synthase (iNOS) gene. This suggests that excess production of iNOS-derived NO is likely to contribute to exaggerated inflammation in the PiZZ individuals lungs during episodes of infection which may contribute to progression of their lung disease.

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