This study investigates whether KMUP-l protects soluble guanylate cyclase (sGC) and inhibits vascular endothelial growth factor (VEGF) expression in lung epithelial cells in hypo xia, therapeutically targeting epithelial proinflammation. H441 cells were used as a representative epithelial cell line to examine the role of sGC and VEGF in hypo xia and the anti-proinflammatory activity of KMUP-l in normoxia. Human H441 cells were grown in hypoxia for 24-72 h. KMUP-l (1, 10, 100 J.1M) arrested cells at the GO/Gl phase of th e cell cycle, reduced cell surv ival and migration, increased p211p27, restored eNOS, increased soluble guanylate cyclase (sGC) and PKG and inhibited Rho kinase II (ROCK-II). KM UP-l (0.001-0.1 J.1M) concentration dependently increased eNOS in normoxia and did not inhibit phosphodiesterase-SA (POE-SA) in hypo xic cells. Hypo xia-induced factor-In (HIF-la) and VEGF were suppressed by KMUP-l but not by L-NAME (100 J.1M). The PKG inhibitor Rp-8-CPT-cGMPS (10 J.1M) blunted the inhibition of ROCK-II by KMUP-l. KMUP-l inhibited thromboxane A2-mimetic agonist U46619-induced POE-SA, TNF-a (100 ng/ml)-induced iNOS, and ROCK-II and associated phospho-p38 MAPK, suggesti ng multiple anti-proinflammatory activ ities. In addition, increased p211p27 by KMUP-l at higher concentrations might contribute to an increased Bax/BcI-2 and active caspase-3/procaspase-3 ratio, concomitantly causing apoptosis. KMUP-l inhibited ROCK-IINEGF in hypoxia, indicating its anti-neoplastic and anti-inflammatory properties. KMUP-l inhibited TNF-a-induced iNOS and U46619-induced POE-S A and phospho-p38 MAPK in normoxia, confirming its anti-proinflammatory action. KMUP-l could be used as an anti-proinflammatory agent to reduce epithelial inflammation.Lung epithelial cells are norm ally well oxygenated but may be exposed to hypoxia in many pathological conditions, including chronic obstructive pulmonary diseases (Ca PO) (1). A phosp hodies terase (POE) inhibitor sildenafil, also a cGMP-enhancer, atte nuated chronic airway inflammation and pulmonary hypertension (2). Targeting the vascul ar endothelial growth factor (VEGF) receptor is not merely limited to cancer therapy but also as an adjunct to existi ng inflammation treatment (3). KMUP -l stimulated endothelial NO and displayed cGMP-dependent inhib ition of Rho kina se (ROCK)