Lung rejection
Upregulation of chemokines in bronchoalveolar lavage fluid as a predictive marker of post-transplant airway obliteration

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Abstract

Background:

The early stage of post-transplant obliterative bronchiolitis (OB) is characterized by an influx of inflammatory cells to the lung, among which neutrophils may play a role in key events. The potential for chemokines to induce leukocyte accumulation in the alveolar space was investigated. We assessed whether changes in the chemotactic expression profile could be used as sensitive markers of the onset of OB.

Methods:

Serial bronchoalveolar lavage (BAL) fluids from 13 stable healthy recipients and 8 patients who developed bronchiolitis obliterans syndrome (BOS) were analyzed longitudinally for concentrations of interleukin-8 (IL-8), chemokines regulated-upon-activation and normal T-cell expressed and secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). These were assessed by enzyme-linked immunosorbent assay (ELISA).

Results:

Significantly elevated percentages of BAL neutrophils and IL-8 levels were found at the pre-clinical stage of BOS, on average 151 ± 164 days and 307 ± 266 days, respectively, before diagnosis of BOS. There was also early upregulation of RANTES and MCP-1 in the BOS group (mean 253 ± 323 and 152 ± 80 days, respectively, before diagnosis of BOS). The level of MCP-1 was consistently higher than that of RANTES until airway obliteration. BAL sICAM-1 and sVCAM-1 levels were not statistically different between the groups.

Conclusions:

These data support the belief that RANTES, IL-8 and MCP-1 play a crucial role in the pathogenesis of OB. The results show that relevant increased levels of such chemokines may predict BOS, and suggest that there is potential for some of these markers to be used as early and sensitive markers of the onset of BOS. Longitudinal monitoring of these chemokine signals may contribute to better management of patients at risk for developing OB, at a stage when remodeling can either be reversed or altered.

Section snippets

Transplant population

Starting in January 1997, we enrolled in a prospective cohort study all patients who underwent a double lung or heart–lung allograft at our institution. Twenty-one consecutive recipients who survived at least 1 year after the transplantation procedure were evaluated up to June 2000. Informed consent was obtained from the patients. The patients’ underlying diseases were cystic fibrosis (n = 9), bronchectasis (n = 2), emphysema (n = 4), primary pulmonary hypertension (n = 1), Eisenmenger syndrome

Results

The median time of follow-up was 627 days (range 428 to 1,460) during which a total of 137 BAL samples (median 6 tests/patient, range 5 to 15) obtained from 21 lung transplant recipients were analyzed. The number of patients and (samples) in each group were as follows: 13 stable healthy recipients free from BOS (n = 70); and 8 recipients suffering from BOS during follow-up (n = 67, including 50 samples obtained during the pre-BOS diagnostic phase, and 17 samples obtained during the post-BOS

Discussion

Post-transplant obliterative bronchiolitis results from a chronic immunologic/inflammatory insult to distal airways that leads to fibroproliferation and obliteration of the luminal space of the allograft. Although the mechanism by which this fibrotic response in OB is believed to be multi-factorial and involves various inflammatory cells, the persistence of recruitment and of activation of neutrophils in the alveolar space has been suggested as one of them.9, 10, 11, 12 Indeed,

Acknowledgements

The authors thank J.F. Dumon, B. Meric, P. Cau and L. Garbe for their excellent technical assistance, and A.L. Flori and N. Morati for providing the data acquisition system.

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    Supported by the Assistance Publique, Hôpitaux de Marseille.

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