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-alpha and interleukin-10.
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)-alpha 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-alpha were higher in LTx patients than in control subjects (p < 0.04, all comparisons). The MMP-9, MMP-9:TIMP-1, and TNF-alpha 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-alpha 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-alpha whereas IL-10 might elicit anti-inflammatory effects through different pathways.
Beeh
K M
KM
Pulmonary Department, Internal Medicine, University Hospital, Mainz, Germany. k.beeh@3-med.klinik.uni-mainz.de
Beier
J
J
Kornmann
O
O
Micke
P
P
Buhl
R
R
D000293:Adolescent; D000328:Adult; D000402:Airway Obstruction / Q000201:enzymology* / Q000209:etiology; D006084:Graft Rejection / Q000201:enzymology; D006801:Humans; D007124:Immunoenzyme Techniques; D016753:Interleukin-10 / Q000032:analysis*; D016040:Lung Transplantation; D020780:Matrix Metalloproteinase 9 / Q000032:analysis*; D008875:Middle Aged; D011183:Postoperative Complications; D013183:Sputum / Q000737:chemistry* / Q000166:cytology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D020780:Matrix Metalloproteinase 9