Increased endothelin-1 associated with bacterial infection in lung transplant recipients.

BACKGROUND: Endothelin-1 (ET-1) has fibrogenic and inflammatory properties. Its pathogenic role in pulmonary fibrosis and certain inflammatory airway diseases is now well known. Its production is, in part, triggered by infectious processes. Episodes of infection are suspected to be involved in the development of bronchiolitis obliterans syndrome (BOS), which is the main feature of chronic lung rejection and the major factor limiting the long-term survival of transplanted patients. We postulated that ET-1 is upregulated during infectious complications arising from the graft and that this could partly explain the remodeling of airway structures observed in BOS. We, therefore, set up this study to assess ET-1 expression in relation to complications of the graft in human lung transplant recipients. METHODS: ET-1 mRNA was quantified by reverse transcription-competitive polymerase chain reaction in cells from 119 samples of bronchoalveolar lavage (BAL) fluid from 17 lung transplant recipients. ET-1 and big ET-1 proteins were assessed in BAL cell culture supernatants by enzyme immunoassay. Transbronchial biopsies (n=21) were stained immunohistochemically for ET-1 receptors. RESULTS: Episodes of bacterial infection strongly correlated with increased ET-1 mRNA and protein expression. ET-1 receptors were also upregulated during these episodes, especially on endothelial and smooth muscle cells. Five of the seven patients with the highest ET-1 levels subsequently developed BOS. CONCLUSIONS: These results raise the possibility that ET-1, part of whose production is triggered by infectious postgraft complications, might play a role in the development of BOS through its potential effects on airway remodeling.

Insulinlike growth factor-1 in lung transplants with obliterative bronchiolitis.

Bronchiolitis obliterans syndrome (BOS) is the major complication limiting survival of lung transplant recipients (Tx patients). The mechanisms underlying this fibrotic process are not known. We assessed IGF-1 and IGFBP-3 expression, critical mediators in different models of pulmonary fibrosis, in nine Tx patients. Three of them developed a BOS at 8, 14, and 17 mo postgraft, respectively. Two of the remaining six displayed a recurrent cytomegalovirus (CMV) infection, and four are in stable condition. IGF-1 mRNA expression was quantitated by RT-PCR in cells from four to six BAL per patient performed during the first 6 mo postgraft. Contrasting with a constantly low expression of IGF-1 mRNA in BAL cells from the six patients without BOS, the three patients with BOS presented marked peaks of IGF-1 on two to five occasions during the study period. These peaks, 3- to 13-fold increased compared with values from the former patients, preceded the diagnosis of BOS by 7, 13, and 17 mo, respectively. On the other hand, IGFBP-3 was highly and exclusively expressed in the three patients with BOS, the mRNA as well as the gene product as demonstrated by Western blotting. Our data strongly argue for a role of IGF-1 and IGFBP-3 in the fibrotic process underlying BOS, and for their possible value as an early marker of this complication.

Peaks of transforming growth factor-beta mRNA in alveolar cells of lung transplant recipients as an early marker of chronic rejection.

BACKGROUND: Chronic lung rejection (CLR) induces a fibroproliferative disorder leading to the occlusion of small airways. It has emerged as the major factor limiting the survival of lung transplant recipients. Predictive markers of CLR are lacking, and its diagnosis is generally ascertained when the fibrosis process is irreversible. METHODS: We have quantified the expression of transforming growth factor-beta (TGF-beta), a critical mediator of fibrogenesis, in alveolar cells from lung transplant recipients using a competitive reverse transcriptase polymerase chain reaction method. RESULTS: We have shown that patients with CLR presented marked peaks of TGF-beta mRNA expression, in contrast with patients without CLR. These peaks preceded the diagnosis of CLR by several months in two of three patients who died within 2 years of diagnosis. CONCLUSIONS: Our data suggest that TGF-beta expression in alveolar cells could serve as an early predictive and prognostic marker of chronic lung rejection.