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Science Forum Index » Life Extension Forum » How NSAIDs may block resolution of inflammatory...
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 Posted: Sat Jun 07, 2008 1:53 am |
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and lead to a chronic inflammatory state in milder cases ...
Arthritis Rheum. 2008 May;58(5):1485-95.
Arthritis develops but fails to resolve during inhibition of
cyclooxygenase 2 in a murine model of Lyme disease.
Blaho VA, Mitchell WJ, Brown CR.
University of Missouri, Columbia, MO 65211, USA.
OBJECTIVE: Recent studies have implicated products of cyclooxygenase 2
(COX-2) in not only induction but also resolution of the inflammatory
response; however, the contribution of COX-2 products to the in vivo
response to infection is unknown. The aim of this study was to
determine the contribution of COX-2 to temporal regulation of the
inflammatory response to infection in a murine model of Lyme
arthritis. METHODS: Experimental Lyme disease was induced in both
arthritis-resistant DBA/2J and arthritis-susceptible C3H/HeJ mice by
inoculation in the hind footpads with Borrelia burgdorferi. COX-2
inhibitors were administered daily, and their effect on arthritis
pathology was assessed at various time points postinfection. The COX-2
deficiency was also backcrossed onto both DBA and C3H backgrounds to
confirm the findings from COX-2 inhibitor-treated mice. RESULTS: In
COX-2 inhibitor-treated or COX-2-/- C3H mice, arthritis developed
normally but did not resolve. Cessation of COX-2 inhibitor treatment
on day 14 postinfection did not induce resolution of arthritis,
indicating an early onset for the molecular mechanisms governing
resolution. The lack of resolution of arthritis correlated with
altered COX-2 and cytosolic phospholipase A2 messenger RNA levels in
the joints of C3H mice. In addition, the proresolution lipid molecule
15-deoxy-Delta12,14-prostaglandin J2 was produced in response to B
burgdorferi infection, and its production was attenuated by the
inhibition of COX-2. CONCLUSION: Our results demonstrate that early
production of COX-2 products is necessary for resolution of the
inflammatory arthritis induced by Borrelia infection, and that COX-2
inhibition may result in prolonged inflammatory states, possibly by
inhibition of proresolution eicosanoids.
PMID: 18438879
Toxicol Appl Pharmacol. 2008 Apr 15;228(2):225-38. Epub 2008 Jan 3.
Secretory phospholipase A2 mediates progression of acute liver injury
in the absence of sufficient cyclooxygenase-2.
Bhave VS, Donthamsetty S, Latendresse JR, Muskhelishvili L, Mehendale
HM.
Department of Toxicology, College of Pharmacy, University of Louisiana
at Monroe, 700 University Avenue, Monroe, LA 71209, USA.
Previous studies have shown that injury initiated by toxicants
progresses even after most of the toxicant is eliminated from the
body. One mechanism of progression of injury is the extracellular
appearance of hydrolytic enzymes following leakage or upon cell lyses.
Under normal conditions, after exposure to low to moderate doses of
toxicants, secretory phospholipase A(2) (sPLA(2)) and other hydrolytic
enzymes are known to appear in the extracellular spaces in order to
cleanup the post-necrotic debris in tissues. We tested the hypothesis
that sPLA(2) contributes to progression of toxicant-initiated liver
injury because of hydrolysis of membrane phospholipids of hepatocytes
in the perinecrotic areas in the absence of sufficient
cyclooxygenase-2 (COX-2). Male Sprague-Dawley rats were administered
either a moderately hepatotoxic dose (MD, 2 ml CCl(4)/kg, ip) or a
highly hepatotoxic dose (HD, 3 ml CCl(4)/kg, ip) of CCl(4). After MD,
liver sPLA(2) and COX-2 were co-localized in the necrotic and
perinecrotic areas and their activities in plasma and liver increased
before decreasing in tandem with liver injury (ALT and histopathology)
leading to 100% survival. In contrast, after the HD, high
extracellular and hepatic sPLA(2) activities were accompanied by
minimal COX-2 activity and localization in the liver throughout the
time course. This led to progression of liver injury and 70%
mortality. These data suggested a destructive role of sPLA(2) in the
absence of sufficient COX-2. Time- and dose-dependent destruction of
hepatocytes by sPLA(2) in isolated hepatocyte incubations confirmed
the destructive ability of sPLA(2) when present extracellularly,
suggesting its ability to spread injury in vivo. These findings
suggest that sPLA(2), secreted for cleanup of necrotic debris upon
initiation of hepatic necrosis, requires the co-presence of
sufficiently induced COX-2 activity to prevent the run-away
destructive action of sPLA(2) in the absence of the tissue protective
mechanisms afforded by COX-2 induction.
PMID: 18329682
Toxicol Appl Pharmacol. 2008 Apr 15;228(2):239-46. Epub 2008 Jan 4.
Inhibition of cyclooxygenase-2 aggravates secretory phospholipase A2-
mediated progression of acute liver injury.
Bhave VS, Donthamsetty S, Latendresse JR, Mehendale HM.
Department of Toxicology, College of Pharmacy, University of Louisiana
at Monroe, 700 University Avenue, Monroe, LA 71209, USA.
Our previous study [Bhave, V. S., Donthamsetty, S., Latendresse, J.
R., Muskhelishvili, L., and Mehendale, H. M. 2008-this issue.
Secretory phospholipase A(2) mediates progression of acute liver
injury in the absence of sufficient COX-2. Toxicol Appl Pharmacol]
showed that in the absence of sufficient induction and co-presence of
cyclooxygenase-2 (COX-2), secretory phospholipase A(2) (sPLA(2))
appearing in the intercellular spaces for cleanup of post-necrotic
debris seems to contribute to the progression of toxicant-initiated
liver injury, possibly by hydrolysis of membrane phospholipids of
hepatocytes in the perinecrotic areas. To further test our hypothesis
on the protective role of COX-2, male Fisher-344 rats were
administered a selective COX-2 inhibitor, NS-398, and then challenged
with a moderately toxic dose of CCl(4). This led to a 5-fold increase
in the susceptibility of the COX-2 inhibited rats to CCl(4)
hepatotoxicity and mortality. The CCl(4) bioactivating enzyme CYP2E1
protein, CYP2E1 enzyme activity, and the (14)CCl(4)-derived radiolabel
covalently bound to the liver proteins were unaffected by the COX-2
inhibitor suggesting that the increased hepatotoxic sensitivity of the
COX-2 inhibited rats was not due to higher bioactivation of CCl(4).
Further investigation showed that this increased mortality was due to
higher plasma and hepatic sPLA(2) activities, inhibited PGE(2)
production, and progression of liver injury as compared to the non-
intervened rats(.) In conclusion, inhibition of COX-2 mitigates the
tissue protective mechanisms associated with COX-2 induction, which
promotes sPLA(2)-mediated progression of liver injury in an acute
liver toxicity model. Because increased sPLA(2) activity in the
intercellular space is associated with increased progression of
injury, and induced COX-2 is associated with hepatoprotection, ratios
of hepatic COX-2 and sPLA(2) activities may turn out to be a useful
tool in predicting the extent of hepatotoxicities.
PMID: 18336855 |
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