Volume 115, Issue 1, Pages 101-109 (July 1998) Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: Implications for gastrointestinal toxicity  John L. Wallace*, Adrian Bak‡, Webb McKnight*, Samuel Asfaha*, Keith A. Sharkey§, Wallace K. MacNaughton§  Gastroenterology  Volume 115, Issue 1, Pages 101-109 (July 1998) DOI: 10.1016/S0016-5085(98)70370-1 Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 1 (A) Effects of various inhibitors of COX (indomethacin, ■; nimesulide, □ etodolac, ▴; NS-398, ○; and DuP697, ●) on carrageenan-induced paw edema in the rat. Each point represents the mean for 5 rats. The percent reduction of edema was calculated from the area under dose-response curves, in comparison to groups of rats treated with the vehicle. The lowest doses of each drug producing a statistically significant (P < 0.05) reduction of edema are listed in Table 2. (B) Correlation between reduction of carrageenan-induced edema by the drugs shown in A and their effects on systemic COX-1 activity. Each point represents the mean data for 5 rats. r2 = 0.934; P < 0.0001. Gastroenterology 1998 115, 101-109DOI: (10.1016/S0016-5085(98)70370-1) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 2 Suppression of (A) COX-1 and (B) COX-2 in rat whole blood by four COX inhibitors (indomethacin, etodolac, NS-398, and nimesulide). Each COX inhibitor was given orally at 3 or 30 mg/kg 6 hours before the blood samples were drawn. Each group consisted of 5–7 rats. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with vehicle-treated group. Gastroenterology 1998 115, 101-109DOI: (10.1016/S0016-5085(98)70370-1) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 3 Suppression of PG synthesis in the (A) footpad (site of inflammation) and (B) stomach of rats by four COX inhibitors. Each COX inhibitor was given orally at 3 or 30 mg/kg 6 hours before the tissue samples were taken. Each group consisted of 5 rats. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with vehicle-treated group. Gastroenterology 1998 115, 101-109DOI: (10.1016/S0016-5085(98)70370-1) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 4 Severity of gastric damage observed 3 hours after oral administration of one of four COX inhibitors. Each test drug was given at the lowest effective anti-inflammatory dose (indomethacin, 3 mg/kg; etodolac, 10 mg/kg; NS-398, 30 mg/kg; and nimesulide, 30 mg/kg). Each group consisted of 11 rats. *P < 0.05 and ***P < 0.001 compared with vehicle-treated group. Gastroenterology 1998 115, 101-109DOI: (10.1016/S0016-5085(98)70370-1) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 5 (A) Inhibition of carrageenan-induced acute inflammation in COX-2–deficient (open symbols) and wild-type (solid symbols) mice by indomethacin (3 mg/kg) but not by NS-398 (30 mg/kg). All of the points in the indomethacin-treated groups were significantly (P < 0.05) lower than the corresponding points in the vehicle-treated groups. (B) Inhibition of PG synthesis in the footpad (site of inflammation) and stomach of COX-2–deficient (□) and wild-type (■) mice by indomethacin (3 mg/kg; Indo) but not by NS-398 (30 mg/kg). **P < 0.01 compared with the corresponding vehicle-treated group. Gastroenterology 1998 115, 101-109DOI: (10.1016/S0016-5085(98)70370-1) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 6 Immunohistochemical staining of sections of the footpad from wild-type mice and mice in which the gene for COX-2 was disrupted. Staining for COX-1 in (A) wild-type and (B) COX-2–deficient mice. Staining for COX-1 is apparent throughout both sections but is more intense in the dermis. Staining for COX-2 in the (C) normal and (D) COX-2–deficient mice. Staining for COX-2 is concentrated in the infiltrating cells within the subdermal region in the footpad from the normal mouse but is absent in the footpad from the COX-2–deficient mouse. However, infiltrating cells (primarily neutrophils) are apparent within the subdermal region of the footpad of the COX-2–deficient mouse. These images are representative of sections taken from 5 mice in each group (bar = 100 μm). Gastroenterology 1998 115, 101-109DOI: (10.1016/S0016-5085(98)70370-1) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 7 Inflammation of the paw of COX-2–deficient (□) and wild-type (■) mice 1 week after injection of carrageenan. Paw volume and thickness were significantly increased in the COX-2–deficient mice, whereas they were unchanged in the normal littermates. Each bar represents the mean ± SEM for 5 mice per group. δP < 0.05 and δδP < 0.01 vs. wild-type group. **P < 0.01 and ***P < 0.001 compared with corresponding basal data. Gastroenterology 1998 115, 101-109DOI: (10.1016/S0016-5085(98)70370-1) Copyright © 1998 American Gastroenterological Association Terms and Conditions