Angiotensin-converting enzyme 2 (ACE2) is the binding-site and entry-point for SARS-CoV-2 in human and highly expressed in the lung. Cigarette smoking (CS) is the leading cause of pulmonary and cardiovascular diseases. Chronic CS leads to upregulation of bronchial ACE2 inducing a high vulnerability in COVID-19 smoker patients. Interestingly, CS-induced dysregulation of pulmonary renin-angiotensin system (RAS) in part contributing into the potential pathogenesis COVID-19 pneumonia and acute respiratory distress syndrome (ARDS). Since, CS-mediated ACE2 activations is not the main pathway for increasing the risk of COVID-19, it appeared that AngII/AT1R might induce an inflammatory-burst in COVID-19 response by up-regulating cyclic nucleotide phosphodiesterase type 4 (PDE4), which hydrolyses specifically the second intracellular messenger 3′, 5′-cyclic AMP (cAMP). It must be pointed out that CS might induce PDE4 up-regulation similarly to the COVID-19 inflammation, and therefore could potentiate COVID-19 inflammation opening the potential therapeutic effects of PDE4 inhibitor in both COVID-19-inflammation and CS.