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Evidence for
oxidative stress in bronchiolitis obliterans syndrome after lung and
heart-lung transplantation
Behr, Juergen; Maier, Konrad; Braun, Barbara; Schwaiblmair, Martin;
Vogelmeier, Claus
Transplantation: Volume 69(9)15 May 2000 pp 1856-1860
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ABSTRACT
Bronchiolitis obliterans
syndrome (BOS) is the most serious long-term sequel of lung or
heart-lung transplantation (H/LTX). Neutrophilia in the lower
respiratory tract is a prominent feature of BOS. Because
polymorphonuclear leukocytes (PMN) are capable of releasing large
quantities of reactive oxygen species, we measured indicators of
oxidative stress and glutathione levels representing antioxidant defense
in H/LTX patients (HLTX, n=6; double-LTX, n=7; single-LTX, n=9). We
analyzed 19 bronchoalveolar lavage (BAL) samples from 13 non-BOS
patients (nine female, four male: age 39±4 years) and 17 BAL samples
from nine BOS patients (five female, four male: age 33±2 years). PMN
were the predominant BAL cell population in BOS (61.7±7.8% vs.
12.3±3.4%, P <0.001). Myeloperoxidase activity in the epithelial lining
fluid and oxidized methionine residues in BAL-derived proteins were
elevated in BOS (8.6±1.6 U/ml vs. 2.2±0.6 U/ml, P <0.01; and 12.6±1.1%
vs. 7.7±0.8%, P <0.001, respectively). In addition, the concentration of
reduced glutathione in epithelial lining fluid was decreased in BOS
(162.6±20.1 M vs. 345.8±57.1 M, P <0.01), whereas the proportion of
oxidized glutathione was increased (13.9±2.0% vs. 6.7±1.2%, P <0.001).
PMN, myeloperoxidase, and oxidized methionine residues were inversely
correlated, whereas reduced glutathione was positively correlated with
forced expiratory volume in 1 sec (P <0.05 to P <0.001). We conclude
that excessive oxidative stress and a lack of glutathione are associated
with BOS after H/LTX and may play relevant roles in the development of
this disorder.
During the last decade, lung transplantation has gained widespread
acceptance as a therapeutic option for a diverse array of advanced lung
diseases. Although refinements of patient selection, operation
procedure, immunosuppression, and posttransplantation care have led to
an improvement of quality of life and survival, the 5-year actuarial
survival after lung transplantation of 42.6% (1) is still
unsatisfactory. A major obstacle for improved long-term survival rates
is the development of bronchiolitis obliterans syndrome (BOS). BOS is
the single most important cause of disablement and death in
long-term survivors of lung transplantation (1, 2). In patients who
survive for 5 years, BOS is found in as much as 60-70% (2). The
pathogenesis of BOS is as yet unclear. Chronic rejection is thought to
be the underlying process, and acute rejection early after
transplantation is believed to be the most important risk factor (2-5).
However, augmentation of immunosuppression is only temporarily
successful in some of the afflicted patients (3-5). In addition,
infections like cytomegalovirus (CMV) infection may aggravate or
initiate the development of BOS, underlining the need for antiinfectious
prophylaxis (4, 5).
Accumulation of polymorphonuclear leukocytes (PMN) in the lower
respiratory tract has been reported to be a general feature of BOS, and
infiltration of bronchial
epithelium by neutrophils has been observed (6, 7). Because PMN are
capable of releasing, among other toxic factors, large amounts of
reactive oxygen species (ROS), we hypothesized that oxidative stress,
not adequately counterbalanced by antioxidants may contribute to the
evolution of BOS after H/LTX. Therefore, we analyzed the
oxidant/antioxidant balance in the lower respiratory tract of patients
after lung and heart-lung transplantation with and without manifest BOS,
as assessed by lung function criteria (8).
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