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.
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.
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.
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.