Iron overload and nitric oxide-derived oxidative stress following lung transplantation

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Abstract

Background: Reactive oxygen species (ROS) may contribute to airway injury and the development of the bronchiolitis obliterans syndrome (BOS) following lung transplantation (LT). Chemically active iron released from ferritin stores and nitric oxide (NO)-derived radicals may add to the oxidative burden.

Methods: We determined the concentrations of ferritin and the aqueous NO derivative nitrite (NO2) within bronchoalveolar lavage fluid (BALF) of 14 stable LT recipients (ST) and 7 subjects with BOS and 21 normal controls. We also assessed the relationship between BALF ferritin and hemosiderin-laden macrophages (HLMs) using a hemosiderin score (HS) and determined BALF albumin concentration as a marker of microvascular leakage.

Results: BALF ferritin concentrations and HSs were significantly elevated in LT recipients overall compared with normal controls (p < 0.05). BALF NO2 levels were elevated in BOS subjects and STs compared with normal controls (p = 0.002 and p = 0.09, respectively), but there was no difference between transplant groups. BALF albumin concentrations were elevated in BOS patients compared with normal controls (p = 0.02) and ST (p = 0.05), but there was no difference between STs and controls. There was a significant relationship between BALF ferritin concentration and HS in LT recipients overall (r(s) = 0.7, p < 0.001). In BOS subjects, but not ST, BALF ferritin was significantly related to BALF albumin (r(s) = 0.8, p = 0.05) and there was a weak relationship with NO2 concentration (r(s) = 0.6, p = 0.1). BALF NO2 was strongly related to BAL %neutrophils in BOS subjects (r(s) = 0.9, p < 0.01), but there was no such relationship in STs.

Conclusions: Our findings suggest that the allograft could be subject to significant iron-generated oxidative stress, which may be exacerbated by NO and neutrophil-derived ROS, particularly in BOS. Microvascular leakage may be a feature of established chronic rejection, which potentiates the iron overload and contributes to further airway damage and remodeling.

Section snippets

Subjects and equipment

BALF samples from 21 subjects who had undergone LT at the Alfred Hospital between March 1991 and October 1994 were studied TABLE I, TABLE II. Among the study population, presence of BOS was defined as a “fixed” 20% or greater fall in forced expiratory volume in 1 second (FEV1) from the best achieved post-transplant in the absence of any other identifiable cause. Stable transplant recipients were defined as those who were clinically well, had well-preserved lung function (i.e., within 20% of

Hemosiderin score (HS) and BAL cell differentials

BAL cells from 19 of the 21 transplant subjects and 3 of the 11 controls examined stained positively for hemosiderin within macrophages (Figure 1 and Table III). HS was significantly higher in both ST (median 10.5, range 0 to 187) and BOS subjects (median 6.5, range 0 to 27) compared with normal controls (median 0, range 0 to 2; p = 0.001 and p = 0.01, respectively). The percentage of cells positive for hemosiderin was also significantly higher in ST (median 7.5%, range 0% to 74.5%) and BOS

Discussion

The current study demonstrates a significant increase in BALF ferritin concentration and HLM numbers in the lower respiratory tract of lung transplant recipients (LTRs). We believe these findings are very unlikely to just be the sequelae of previous biopsy procedures. In addition, we found elevated levels of nitrite in BALF of LTRs, suggesting the allograft may be subject to significant iron and NO-derived free-radical damage. Furthermore, we confirmed previous observations that BAL

References (42)

  • V.G. Valentine et al.

    Actuarial survival of heart-lung and bilateral sequential lung transplant recipients with obliterative bronchiolitis

    J Heart Lung Transplant

    (1996)
  • S.A. Yousem et al.

    Efficacy of transbronchial lung biopsy in the diagnosis of bronchiolitis obliterans in heart-lung transplant recipients

    Transplantation

    (1989)
  • S.A. Yousem et al.

    Architectural remodelling of lung allografts in acute and chronic rejection

    Arch Pathol Lab Med

    (1992)
  • G.C. Riise et al.

    Bronchiolitis obliterans syndrome in lung transplant recipients is associated with increased neutrophil activity and decreased anti-oxidant status in the lung

    Eur Resp J

    (1998)
  • R.S. Britton et al.

    Mechanisms of iron toxicity

  • D. Saleh et al.

    Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthaseeffect of inhaled glucocorticoid

    FASEB J

    (1998)
  • A. Giaid et al.

    Expression of nitric oxide synthase in lung transplant recipients with bronchiolitis obliterans

    Eur Respir J

    (1995)
  • E. Gabbay et al.

    In stable lung transplant recipients, exhaled nitric oxide levels positively correlate with airway neutrophilia and bronchial epithelial iNOS

    Am Rev Respir Crit Care Med

    (1999)
  • J. Devlin et al.

    Nitric oxide generationa predictive parameter of acute allograft rejection

    Transplantation

    (1996)
  • C.C. Miller et al.

    Iron-independent induction of ferritin H-chain by tumor necrosis factor

    Proc Natl Acad Sci USA

    (1991)
  • J.L. Corhay et al.

    Iron content in human alveolar macrophages

    Eur

    (Respir J 1992)
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