Selective cyclooxygenase inhibition by SC-560 improves hepatopulmonary syndrome in cirrhotic rats

Abstract

ObjectiveHepatopulmonary syndrome (HPS) is characterized by hypoxia in patients with chronic liver disease. The mechanism of HPS includes pulmonary vasodilatation, inflammation, and angiogenesis. Prostaglandins synthesized by cyclooxygenases (COX) participate in vascular responsiveness, inflammation and angiogenesis, which can be modulated by COX inhibitors. We therefore evaluated the impact of COX inhibition in rats with common bile duct ligation (CBDL)-induced liver cirrhosis and HPS.MethodsCirrhotic rats were randomly allocated to receive non-selective COX inhibitor (indomethacin), selective COX-1 inhibitor (SC-560), or COX-2 inhibitor (celecoxib) for 14 days. After that, hemodynamic parameters, severity of hypoxia and intrapulmonary shunts, liver and renal biochemistry parameters, histological finding and protein expressions were evaluated.ResultsNon-selective COX inhibition by indomethacin improved hepatic fibrosis and pulmonary inflammation in cirrhotic rats with HPS. It also decreased mean arterial blood pressure, portal pressure, and alleviated hypoxia and intrapulmonary shunts. However, indomethacin increased mortality rate. In contrast, selective COX inhibitors neither affected hemodynamics nor increased mortality rate. Hypoxia was improved by SC-560 and celecoxib. In addition, SC-560 decreased intrapulmonary shunts, attenuated pulmonary inflammation and angiogenesis through down-regulating COX-, NFκB- and VEGF-mediated pathways.ConclusionSelective COX-1 inhibitor ameliorated HPS by mitigating hypoxia and intrapulmonary shunts, which are related to anti-inflammation and anti-angiogenesis.

Effects of a cyclooxygenase-1-selective inhibitor in combination with taxol or cisplatin on cyclin D1, apoptosis, and vascular endothelial growth factor in a xenograft model of ovarian cancer

“…COX-1 is involved in the regulation of angiogenesis, positively correlated with the expression of VEGF, while inhibition of COX-1 can reverse this relevance [21]. SC-560 can inhibit tumor angiogenesis by inhibiting COX-1 expression [11], the pivotal mechanism is related to decrease tumor-associated VEGF expression [20,22] and the expression of MDR1 P-glycoprotein (Pgp). The VEGF mRNA expression level in SC-560 group was significantly suppressed, which was different from the control group in present study.There were synergistic repressions on expression of VEGF mRNA in SC-560 + DDP and SC-560 + taxol group.…”

“…The VEGF mRNA expression level in SC-560 group was significantly suppressed, which was different from the control group in present study.There were synergistic repressions on expression of VEGF mRNA in SC-560 + DDP and SC-560 + taxol group. Chang et al [22] found that SC-560 attenuated angiogenesis by downregulating COX-, nuclear factor kappa B-and VEGF-mediated pathways, and improved hepatopulmonary syndrome in cirrhotic rats. A previous report [23] also suggested that ximenynic acid (COX-1-selective inhibitor) reduced the expression level of VEGF-B and VEGF-C.…”

Discovery of Furanone-Based Radiopharmaceuticals for Diagnostic Targeting of COX-1 in Ovarian Cancer

“… 28 , 29 Thus, the COX-1-selective inhibitor SC-560, a diarylpyrazole analog, was discovered via the deletion of the sulfonamide group from celecoxib. 30 SC-560 has been extensively used as an in vivo probe for COX-1’s involvement in biological responses; 31 , 32 however, when [ 11 C]SC-560 was synthesized for PET imaging, COX-1-dependent accumulation in tissues could not be demonstrated. 33 This failure is likely because SC-560 has not been optimized for in vivo activity and suffers from multiple liabilities, including poor solubility and pyrazole-associated off-target effects.…”

“…The diarylheterocyclic scaffolds yielded the highest number of potent and selective COX-2 inhibitors, such as celecoxib, rofecoxib, and valdecoxib (Figure a) . The key determinant of the COX-2 selectivity of these compounds is the presence on one of the aromatic rings of a sulfonamide or a methylsulfone that inserts into a side-pocket in the cyclooxygenase active site that is only accessible in COX-2. , Thus, the COX-1-selective inhibitor SC-560, a diarylpyrazole analog, was discovered via the deletion of the sulfonamide group from celecoxib . SC-560 has been extensively used as an in vivo probe for COX-1’s involvement in biological responses; , however, when [ 11 C]­SC-560 was synthesized for PET imaging, COX-1-dependent accumulation in tissues could not be demonstrated .…”

Shenqi Fuzheng Injection impairs bile duct ligation-induced cholestatic liver injury in vivo

“…This was an important observation since PPAR-γ activation inhibits the expression of several inflammatory response genes, including those of TNF-α and COX-2 [18]. Further, COX-2 was activated following the mobilization of NF-κB signaling in the BDL rat model, and decreased expression of both COX-2 and NF-κB, and thus attenuated inflammation in the BDL-induced rat model [20,21]. Thus, in the present study, we suggest that the protective effect of SFI might be due to inhibition of COX-2 and NF-κB expression by a mechanism that might be partly dependent on up-regulated functional expression of PPAR-γ.…”