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Citation Information: J Clin Invest. 2000;105(4):469-478. https://doi.org/10.1172/JCI6899.
Abstract
To investigate roles in intestinal inflammation for the 2 cyclooxygenase (COX) isoforms, we determined susceptibility to spontaneous and induced acute colitis in mice lacking either the COX-1 or COX-2 isoform. We treated wild-type, COX-1–/–, COX-2–/–, and heterozygous mice with dextran sodium sulfate (DSS) to provoke acute colonic inflammation, and we quantified tissue damage, prostaglandin (PG) E2, and interleukin-1β. No spontaneous gastrointestinal inflammation was detected in mice homozygous for either mutation, despite almost undetectable basal intestinal PGE2 production in COX-1–/– mice. Both COX-1–/– and COX-2–/– mice showed increased susceptibility to a low-dose of DSS that caused mild colonic epithelial injury in wild-type mice. COX-2–/– mice were more susceptible than COX-1–/– mice, and selective pharmacologic blockade of COX-2 potentiated injury in COX-1–/– mice. At a high dose, DSS treatment was fatal to 50% of the animals in each mutant group, but all wild-type mice survived. DSS treatment increased PGE2 intestinal secretion in all groups except COX-2–/– mice. These results demonstrate that COX-1 and COX-2 share a crucial role in the defense of the intestinal mucosa (with inducible COX-2 being perhaps more active during inflammation) and that neither isoform is essential in maintaining mucosal homeostasis in the absence of injurious stimuli.
Authors
Olivier Morteau, Scott G. Morham, Rance Sellon, Levinus A. Dieleman, Robert Langenbach, Oliver Smithies, R. Balfour Sartor
cyclooxygenases and angiogenesis
Submitter: vittorio tomasi | tomasi@alma.unibo.it
university of bologna,dept. of biology
Published September 12, 2000
The arachidonate cascade is one of the most complicate mechanism of signaling so far identified. The substrate , largely derived from the diet, is converted into phospholipids, allowing the organism to maintain stores during dietary deprivations, and it is delivered to endoperoxide forming enzymes by aspecific phospholipase, cytosolic phospholipase A2. CPLA2 activation is complex, since the enzyme has to be translocated to plasma and possibly other membranes in the proximity of the substrate. Cycloxygenases (COX) molecules have surface channels specifically lodging arachidonate and delivering endoperoxide (PGH2) to a myriad of prostanoid forming enzymes (1).
The two isoforms so far identified are encoded by mRNAs having widely different half-lives, therefore COX-1 is commonly described as a constitutively expressed enzyme whereas COX-2 is designed as the inducible isoform. This is clearly an oversimplification as indicated by several recent reports showing, for example, that COX-2 in tumors and in other diseases is actually constitutively expressed (1-3).
One characteristic of arachidonate cascade is the instability of intermediates in aqueous environments : PGH2 decays very rapidly , thromboxane A2 has a half-life of tens of seconds, prostacyclin reaches 5 -10 minutes, and PGD2 is rapidly converted in the cyclopentenone pathway. PGE2, PGF2alfa ,6-keto PGE1 and PGD2 derivatives are more stable in vitro but likely not very stable in vivo.
Thus this system may work optimally if PGH2 is delivered in the proximity of prostanoid-forming enzymes. COX have been considered endoplasmic reticulum enzymes ,however recently at least COX-2 has been shown to rapidly translocate to nuclear envelope (4). This and the fact that novel prostanoid receptors have been identified inside the nucleus , suggest a novel role of prostanoids as intracellular messengers having the capability to regulate gene expression.
The article by Morteau et al (5), showing that no alterations are observable in the gastrointestinal tract of COX1 knock-out mice treated with a COX-2 inhibitor, is surprising. COX-1 is likely to be involved in angiogensis (3), so suppression of the gene should impair angiogenesis and the concomitant inhibition of COX-2 should not permit this isoform to substitute for the missing function. The impairment in angiogenesis could also explain the sensitivity of mice to noxious stimuli.
Morteau et al are urged to check whether circulation in the gastrointestinal tract is viable in their mice or if classical angiogenic stimuli are still able to induce re-modeling of vasculature.
A second important point is that due to the complexity of arachidonate cascade, the determination of just one prostanoid (PGE2) may be misleading, considering also that,once formed, endoperoxide is converted non-enzimatically to PGE2 to a very large extent .It has also been clearly shown that in humans the main product of COX-2 activity is represented by PGI2 which behaves as a very powerful stimulus to initiate angiogenesis (6). Moreover, PGD2 derivatives along the cyclopentenone pathway seem to play novel and significant roles often contrasting the pro-inflammatory roles of classical endoperoxide derivatives (7.8).
The prostanoid field has acquired a great impetus in these last years mainly because of its involvement in several diseases (1). The system which evolution
has selected to participate to homeostatic mechanisms involved in signaling of diseases and in the body protection against noxious stimuli, may be the causative agent of diseases when overexpressed or when down regulated. For example in colon tumors overexpression of COX-2 is likely to be responsible for tumor growth linked to enhanced angiogenesis (2,3) , whereas the down regulation of PGI2 synthase in the lungs greatly contributes to the genesis of primary pulmonary hypertension (9). In both cases pharmacological interventions using either COX-2 specific inhibitors (3,10) or PGI2 stable analogues has produced dramatic improvements in patients (9). I would like finally to mention a case in which a very subtle disregulation of the prostanoid system causes a very common disease, essential hypertension. In the Suita study (11) it was clearly shown that among the several polymorphic forms of the PGI2 synthase gene , two carry weak promoters, rendering individuals with these alleles more prone to hypertension than individuals with strong promoters. Interestingly this observation may expand the use of stable PGI2 analogues to treat essential hypertension.
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