Clinical lung and heart/lung transplantation
Sputum levels of metalloproteinase-9 and tissue inhibitor of metalloproteinase-1, and their ratio correlate with airway obstruction in lung transplant recipients: relation to tumor necrosis factor-α and interleukin-10

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Abstract

Background

Chronic transplant rejection is characterized by progressive narrowing of small airways caused by matrix remodeling and fibrosis. Matrix-metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in the turnover of extracellular matrix.

Methods

To clarify the contribution of MMPs and TIMPs to airway inflammation in patients after lung transplantation (LTx), we used enzyme immunoassays to measure induced sputum concentrations of MMP-9, TIMP-1, and controlling cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-10 of 30 LTx patients and 15 control subjects.

Results

Sputum concentrations of MMP-9, TIMP-1, the MMP-9:TIMP-1 ratio, and TNF-α were higher in LTx patients than in control subjects (p < 0.04, all comparisons). The MMP-9, MMP-9:TIMP-1, and TNF-α levels were also significantly higher in LTx patients with chronic rejection compared with those with stable organ function (p < 0.03, all comparisons), whereas IL-10 levels were higher in the latter group (p = 0.05). In all LTx patients, MMP-9 and the MMP-9:TIMP-1 ratio were negatively correlated with forced expiratory volume in 1 second values (rho = −0.47, p = 0.01, and rho = −0.53, p = 0.003, respectively). We found that MMP-9 positively correlated with sputum neutrophils and TNF-α whereas MMP-9 and TIMP-1 did not correlate with IL-10.

Conclusions

These data underline the possible contribution of proteases such as MMP-9 to chronic transplant rejection, and suggest that an imbalance of MMP-9 and TIMP-1 may be involved in the pathogenesis of airway obstruction after LTx. We found that MMP-mediated inflammation seems to be controlled by TNF-α whereas IL-10 might elicit anti-inflammatory effects through different pathways.

Section snippets

Patients

We entered 30 LTx patients into the study (80% males; mean age, 48 years; range, 18 to 64 years). Indications for transplantation were pulmonary emphysema (n = 13), idiopathic pulmonary fibrosis (n = 9), cystic fibrosis (n = 6), and others (n = 2). Of these, 16 patients had undergone single lung transplantation and 13 patients had undergone double lung transplantation. One patient had undergone single retransplantation after initial double-LTx. Immunosuppressive regimens post-transplantation

Transplant function

According to the International Society for Heart and Lung Transplantation consensus report,24 12 patients met the clinical criteria for chronic transplant rejection, whereas the other 18 had apparently regular graft function. Absolute and relative (% predicted) values of FEV1 and the ratio of FEV1/FVC were significantly lower in LTx patients with chronic rejection (Table I). Sputum cultures were positive for P cepacia in 1 patient with underlying cystic fibrosis, and for S aureus in another

Discussion

Chronic rejection is the major cause limiting overall prognosis of patients after lung transplantation. Transplant rejection is a complex inflammatory process that involves a variety of effector cells and mediators. This study reports the feasibility of using sputum induction to investigate lower respiratory tract inflammation in lung transplant recipients. Consistent with bronchoalveolar lavage and biopsy studies,21, 25 pronounced neutrophilia was present in the airway secretions of LTx

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