Matrix metalloproteases (MMPs) are enzymes involved in the degradation of extracellular matrix (ECM) proteins such as fibronectin and collagen. Tissue inhibitors of metalloproteinases (TIMPs) dampen MMP activity. Lungs of chronic obstructive pulmonary disease (COPD) patients show remodeling including airway fibrosis and emphysema in which MMP and TIMP activity may play a role. The main risk factor for COPD, cigarette smoke, may provoke an imbalance between MMPs and TIMPs. Currently, COPD patients are treated with β 2 ‐ agonists known to elevate cyclic AMP (cAMP). As cAMP modulates MMP9 and TIMP1 expression, activity and secretion, we investigated the potential role of the cAMP effectors protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac) in these effects. Exposure of the human bronchial epithelial cell line 16HBE14o ‐ to cigarette smoke extract (CSE) elevated MMP9 and also the MMP9/TIMP1 ratio. In addition, CSE induced pro ‐ MMP9 as measured by zymography. Direct pharmacological activation of PKA by 6 ‐ Bnz ‐ cAMP reduced CSE ‐ induced MMP9 mRNA, whereas the β 2 ‐ agonist fenoterol was less effective and no effect was observed when Epac was selectively activated by 8 ‐ pCPT ‐ 2' ‐ O ‐ Me ‐ cAMP. The level of pro ‐ MMP9 was reduced by fenoterol. Pharmacological activation of PKA tended to decrease pro ‐ MMP9, whereas Epac activation was not effective. Our findings suggest that cAMP and its effector PKA reduce CSE ‐ induced pro ‐ MMP9, a process accompanied by downregulation of CSE ‐ induced MMP9 mRNA expression by PKA.

markedly amplified by muscarinic agonist-induced PKC activation.