Bronchiolitis Obliterans Syndrome after (Heart–)Lung Transplantation

Abstract

Increased numbers of neutrophils are a common finding in bronchoalveolar lavage fluid (BALF) samples obtained from patients after (heart-)lung transplantation [(H)LTX]. Since proteases and reactive oxygen species secreted by neutrophils are capable of causing substantial damage to the lung tissue if not counterbalanced by the antiprotease and antioxidant screen, we hypothesized that neutrophil products may play a role in the development of obliterative bronchiolitis (OB). A total of 72 BALF samples obtained from 33 patients after (H)LTX were evaluated. Sixteen of these patients were suffering from bronchiolitis obliterans syndrome (BOS) at the time of bronchoalveolar lavage (BAL). As a control, BALF samples from 17 healthy volunteers were analyzed. Anti-neutrophil elastase (NE) activity was quantified by a titration assay. Concentrations of alpha(1)-protease inhibitor (API), secretory leukocyte protease inhibitor (SLPI), NE-API complex, and myeloperoxidase (MPO) were measured by ELISA. Oxidized methionine [Met(O)] was quantified by high-performance liquid chromatography (HPLC). Epithelial lining fluid (ELF) from patients suffering from BOS showed significantly increased neutrophil counts, significantly elevated concentrations of NE-API complex and Met(O), and a significant decrease in the concentration of SLPI. Furthermore, a trend toward an increased NE activity and MPO concentration was observed. These findings suggest that neutrophils may be involved in the development of BOS.

Sleeping Beauty‐based gene therapy with indoleamine 2,3‐dioxygenase inhibits lung allograft fibrosis

“…The precise mechanism(s) for the observed beneficial effect provided by IDO remains obscure, but it appears that IDO inhibits the development of lung fibrosis in multiple ways: ( 1 ) It abolished T cell‐mediated acute cellular rejection (4, 5), a predominant risk for the development of OB (8–10); ( 2 ) IDO with its antiinflammatory and antioxidant property (4, 6) may constitute another way to provide protection against lung allograft fibrosis (11–13); ( 3 ) In the present study, we showed that lung cells overexpressing hIDO could suppress TGF‐β‐stimulated fibroblast proliferation, indicating that IDO may have a direct antifibrotic effect under certain circumstances. These multiple biological activities of IDO likely collaborate to significantly limit the development of transplantation‐associated lung fibrosis.…”

“…In a recent study, we found that transient overexpression of human IDO (hIDO) in transplanted rat lung inhibited alloreactive T cell response and augmented the local defense system against inflammation‐associated oxidative stress, and thereby abrogated acute allograft injury (4). It should be noted that episodes of T cell‐mediated acute rejection (8–10) and inflammation/inflammation‐associated oxidative stress (11–13) are also major risk factors for development of lung allograft fibrotic lesions, e.g ., OB. Thus, IDO with its potent anti‐T cell and antioxidant properties allowed us to hypothesize that prolonged up‐regulation of IDO may provide further protection against not only acute but also chronic lung allograft injury by suppressing “unwanted reactions” such as immune, inflammatory, and fibroproliferative responses.…”

Postinfectious bronchiolitis obliterans in children: lessons from bronchiolitis obliterans after lung transplantation and hematopoietic stem cell transplantation

“…Furthermore, the degree of neutrophil elevation in BAL correlated with the stage of BO after LT 20) . Based on BAL studies of matrix metalloproteinases, reactive oxygen species, and defensins 21 22 23 24 25 26) , Kennedy et al 19) recently proposed that neutrophils play a central role in the pathogenesis of BO after LT. They proposed that epithelial cells injured by diverse posttransplant insults release IL-8 and other proinflammatory cytokines, resulting in the recruitment of inflammatory cells, including neutrophils.…”

A Pilot Study to Investigate the Balance between Proteases and α1-Antitrypsin in Bronchoalveolar Lavage Fluid of Lung Transplant Recipients

“…Numerous reports, in fact, have shown its ability to neutralize a broad range of other serine proteases and different classes of proteases, which include proteinase-3, myeloperoxidase, cathepsin G (Cat. G), metalloproteases and cysteine-aspartic proteases [11,12,13,14,15,16,17].…”