Effects of specific inhibition of cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2 in the rat stomach with normal mucosa and after acid challenge

Gretzer, Britta; Maricic, Nenad; Respondek, Michael; Schuligoi, Rufina; Peskar, B. M.

doi:10.1038/sj.bjp.0703955

Cited by 122 publications

(106 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because transient COX-1 inhibition in control mice that did not receive LPS is not associated with weight loss, our findings suggest that COX-1-generated prostaglandins may serve a protective role during inflammation, such as maintaining gastric mucosal integrity in the face of fasting and stress. This notion is strongly supported by recent studies demonstrating that selective COX-1 inhibition alone does not result in gastric damage, whereas combined COX-1 and COX-2 inhibition, or COX-1 inhibition associated with acid challenge or glucocorticoid administration, does (10,39). The majority of NSAIDs in common clinical use for fever control during infection demonstrate substantial COX-1 inhibitory activity and are likely to cause similar decreases in food intake and body weight maintenance during the recovery phase of illness.…”

Section: Discussionsupporting

confidence: 69%

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

Johnson

Vogt

Burney

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Anorexia and weight loss are frequent complications of acute and chronic infections and result from induction of cytokines, prostaglandins, and other inflammatory mediators that are critical for pathogen elimination. Selective attenuation of the hypophagic response to infection and maintenance of the production of factors essential for infection control would be a useful addition to antimicrobial therapy in the treatment of human disease. Here, we evaluate the relative contribution of cyclooxygenase (COX)-1- and COX-2-derived prostaglandins to anorexia and weight loss precipitated by systemic immune activation by lipopolysaccharide (LPS). Using COX isoform-selective pharmacological inhibitors and gene knockout mice, we found that COX-2 inhibition during LPS-induced inflammation results in preserved food intake and maintenance of body weight, whereas COX-1 inhibition results in augmented and prolonged weight loss. Regulation of neuropeptide Y, corticotropin-releasing hormone, leptin, and interleukin-6 does not change as a function of COX-2 inhibition after LPS administration. Our data implicate COX-2 inhibition as a therapeutic target to maintain nutritional status while still allowing a normal cytokine response during infection.

show abstract

Section: Discussionsupporting

confidence: 69%

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

Johnson

Vogt

Burney

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…at ASPET Journals on May 10, 2018 jpet.aspetjournals.org gastric ulcer healing in rats (Gretzer et al, 2001;Berenguer et al, 2002;Hatazawa et al, 2007), whereas the dose of valdecoxib has been shown to produce a selective COX-2 inhibition in rat (Gierse et al, 2005;Ahmad et al, 2009). For these reasons, the above doses were used in our subsequent experimental procedures.…”

Section: Nsaid-activated Gene and Gastric Ulcer Healing 143mentioning

confidence: 99%

Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Plays a Role in the Impairing Effects of Cyclooxygenase Inhibitors on Gastric Ulcer Healing

Colucci¹,

Antonioli²,

Bernardini³

et al. 2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair gastric ulcer healing. This study investigates the involvement of NSAIDactivated gene-1 (NAG-1) in ulcer repair impairment by cyclooxygenase (COX) inhibitors. Gastric ulcers were induced in rats by acetic acid. Four days later, animals received daily intragastric indomethacin (nonselective COX-1/COX-2 inhibitor; 1 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (selective COX-1 inhibitor; 2.5 mg/kg), (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl) phenyl-2(5H)-furanone (DFU) (selective COX-2 inhibitor; 5 mg/kg), celecoxib (selective COX-2 inhibitor; 1 mg/kg), and valdecoxib (selective COX-2 inhibitor; 1 mg/kg), for 1, 3, or 7 days. Ulcerated tissues were processed to assess: 1) COX-1, COX-2, NAG-1, proliferating cell nuclear antigen (PCNA), and activated caspase-3 expression; 2) ulcer area; and 3) prostaglandin E 2 (PGE 2 ) levels. COX-1 expression in ulcerated tissues was decreased, whereas COX-2 expression was enhanced. Ulcer healing was delayed by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. Ulcer PGE 2 levels were decreased by SC-560, DFU, celecoxib, valdecoxib, and indomethacin. NAG-1 was overexpressed in ulcerated tissues and further enhanced by indomethacin, DFU, and SC-560, but not by celecoxib or valdecoxib. PCNA expression in ulcerated areas was reduced by indomethacin, but not by the other test drugs. The expression of activated caspase-3 in ulcers was increased and enhanced further by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. These findings indicate that: 1) COX inhibitors exert differential impairing effects on gastric ulcer healing, through mechanisms unrelated to the inhibition of COX isoforms and prostaglandin production; and 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing.

show abstract

“…28 -30 Ketorolac (2 mg/kg) preferentially inhibits COX-1, 31 whereas rofecoxib (2 or 20 mg/kg) selectively blocks COX-2. 32 Determination of NOS-II, COX-1, COX-2, and ␤-Actin mRNA Total RNA (50 g) from the heart, lung, and liver was extracted, and the abundance of NOS II mRNA, COX-1 mRNA, and COX-2 mRNA was semi-quantitated and related to ␤-actin mRNA (1 g) by specific RNase protection assay as described. 8,33 Determination of Nitrate/Nitrite, PGE 2 , and 6-Keto PGF 1␣ Nitrate/nitrite concentrations and concentrations of PGE 2 and 6-keto prostaglandinF 1␣ in plasma and liver were determined using commercially available assay kits (Cayman Chemical).…”

Section: Animal Experimentsmentioning

confidence: 99%

Cyclooxygenase-2 Inhibition Attenuates Lipopolysaccharide-Induced Cardiovascular Failure

et al. 2002

View full text Add to dashboard Cite

Abstract-The present study aimed to determine the relevance of cyclooxygenase-2 (COX-2)-derived prostanoids for the adverse effects of lipopolysaccharides (LPSs) on cardiovascular function. For this goal, male Sprague-Dawley rats received a single intravenous dose of LPS (10 mg/kg) and were treated with different cyclooxygenase inhibitors. Injection of LPS caused a marked decrease of systolic arterial pressure, from 128 to 79 mm Hg, and a concomitant increase of heart rate, from 380 to 530 minutes Ϫ1 . Both the decrease of systemic arterial pressure and the increase of heart rate induced by LPS were almost absent if the animals also received the COX-2 blocker rofecoxib (20 mg/kg), regardless whether the drug was given 1 hour before or 1 hour after LPS. Although plasma and organ levels of prostanoids were lowered by rofecoxib, the characteristic LPS-induced increases of NO synthase II and COX-2 gene expression, as well as of plasma and tissue nitrate/nitrite concentrations, were not affected by rofecoxib. Although rofecoxib treatment did also not change LPS-induced tissue cytokine concentrations, it markedly improved LPS-induced liver damage, as indicated by the decrease of transaminases. Moreover, the overall well-being of the LPS-injected animals improved on concomitant treatment with the COX-2 inhibitor. Taken together, our data suggest that COX-2-derived prostanoids are major mediators for the detrimental effects of LPS on cardiovascular and organ function. Key Words: shock Ⅲ cyclooxygenase Ⅲ hemodynamics Ⅲ prostaglandins Ⅲ nitric oxide I t is well known that the release of lipopolysaccharides (LPS) from Gram-negative bacteria into the blood stream (eg, in the course of an infection) causes a number of serious adverse effects, such as an increase of body temperature, decrease of blood pressure, and multiorgan failure. [1][2][3] There is consensus that the first mediators in the cascade of LPSinduced events are cytokines. 1,2 These, in turn, induce the expression of a number of enzymes, generating a second class of mediators, which are meant to support the body's defense against bacterial invaders but also mediate adverse effects. Characteristic cytokine-induced enzymes in this context are the inducible isoforms of NO synthase (NOS-II) and cyclooxygenase-2 (COX-2). 2,4,5 Thus, it is clear that the increase of body temperature and local inflammatory reactions are triggered by COX-2-derived prostanoids. [5][6][7] LPS septicemia leads to cardiovascular failure, as reflected by a strong decrease of arterial blood pressure that is resistant to vasoconstrictor hormones. 8 -12 The mechanisms leading to LPSinduced hypotension have not yet been clearly identified. In view of the ubiquitous and strong stimulation of NO formation through NOS-II, it has been assumed that this particular vasodilator plays the major role for the decrease of arterial resistance. 1,2,4 Moreover, it has been observed that inhibitors of NOS-II such as L-canavanine, S-methylisothiourea, or aminoguanidine attenuate LPS-induced decrease of blood ...

show abstract

Effects of specific inhibition of cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2 in the rat stomach with normal mucosa and after acid challenge

Cited by 122 publications

References 37 publications

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Plays a Role in the Impairing Effects of Cyclooxygenase Inhibitors on Gastric Ulcer Healing

Cyclooxygenase-2 Inhibition Attenuates Lipopolysaccharide-Induced Cardiovascular Failure

Contact Info

Product

Resources

About