Lo CY, et al. - Considering that airway hyperresponsiveness (AHR) is correlated with airway inflammation and a rapid decline in lung function and is a predictor of future risk of COPD among smokers and that alveolar macrophages (AMs) from patients with COPD release a greater amount of matrix metalloproteinase (MMP)-9, researchers determined if the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) is related to airway hyperresponsiveness (AHR) in smokers. They noted excessive production of MMP-9 over TIMP-1 by AMs of nonsmokers with AHR (AHR + NS), which could be a predictor of the development of airway obstruction. Among smokers, inhibition of p38 MAPK and ERK suppresses the generation of MMP-9 by AMs.

Methods

• Researchers recruited healthy smokers with AHR (AHR + S) or smokers without AHR (AHR - S; divided according to a methacholine challenge test) and nonsmokers without AHR (AHR - NS).
• They performed spirometry during recruitment and repeated after 5 years.
• Initially, from bronchoalveolar lavage (BAL) fluid, recovered AMs were cultured in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), MAPK kinase (MEK) 1/2 (the MEK of extracellular signal-regulated kinase [ERK] inhibitor, PD98059), or medium alone for 24 h.
• Using enzyme-linked immunosorbent assay, they measured the release of MMP-9 and TIMP-1 in culture supernatants.

Results

• In the 5-year period, researchers observed a greater reduction in forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC), FEV₁ (as a percentage of the predicted value [%pred]), and maximal mid-expiratory flow (MMEF) among AHR + S.
• A higher proportion of neutrophils and a lower proportion of AMs were noted in BAL fluid recovered from AHR + S.
• AMs from nonsmokers with AHR (AHR + NS) released more MMP-9 and less TIMP-1, with an increase in MMP-9/TIMP-1 ratios compared to AMs from AHR - NS and AHR - S.
• A positive correlation was noted of the MMP-9/TIMP-1 ratio in smokers with the annual decline in FEV₁%pred, FVC%pred, and MMEF%pred.
• In this study, both SB203580 and PD98059 markedly reduced MMP-9, but not TIMP-1, from AMs of smokers.