Anandamide regulates lipopolysaccharide-induced nitric oxide synthesis and tissue damage in the murine uterus

Vercelli, CA; Aisemberg, Julieta; Billi, Silvia; Cervini, Marcos; Ribeiro, Maria L.C.; Farina, Mariana; Franchi, A

doi:10.1016/s1472-6483(10)60033-8

Cited by 27 publications

(42 citation statements)

References 29 publications

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“…We are the first group to show uterine NAPE-PLD changes in the last part of pregnancy in mice. Here we demonstrated that, as we have previously shown for early pregnancy stages (Vercelli et al 2009), LPS increases Nape-pld mRNA and protein expression in the uterus in the late stages of pregnancy. This finding correlates with Liu et al (2003), who have demonstrated that LPS increases NAPE-PLD activity and AEA levels in RAW264.7 mouse macrophages.…”

Section: Discussionsupporting

confidence: 87%

“…Several studies have shown that LPS affects FAAH activity and/or expression. Indeed, incubation of uterine explants from mice in day 7 of pregnancy with LPS increases FAAH activity (Vercelli et al 2009), whereas in human peripheral lymphocytes, LPS downregulates FAAH expression and increases AEA levels (Maccarrone et al 2001). We were unable to detect any changes in FAAH activity in our model of LPSinduced preterm labor.…”

Section: Discussionmentioning

confidence: 71%

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Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

Bariani¹,

Rubio²,

Cella³

et al. 2015

Reproduction

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Prematurity is the leading cause of perinatal morbidity and mortality worldwide. There is a strong causal relationship between infection and preterm births. Intrauterine infection elicits an immune response involving the release of inflammatory mediators like cytokines and prostaglandins (PG) that trigger uterine contractions and parturition events. Anandamide (AEA) is an endogenous ligand for the cannabinoid receptors CB1 and CB2. Similarly to PG, endocannabinoids are implicated in different aspects of reproduction, such as maintenance of pregnancy and parturition. Little is known about the involvement of endocannabinoids on the onset of labor in an infectious milieu. Here, using a mouse model of preterm labor induced by lipopolysaccharide (LPS), we explored changes on the expression of components of endocannabinoid system (ECS). We have also determined whether AEA and CB antagonists alter PG production that induces labor. We observed an increase in uterine N-acylphosphatidylethanolaminespecific phospholipase D expression (NAPE-PLD, the enzyme that synthesizes AEA) upon LPS treatment. Activity of catabolic enzyme fatty acid amide hydrolase (FAAH) did not change significantly. In addition, we also found that LPS modulated uterine cannabinoid receptors expression by downregulating Cb2 mRNA levels and upregulating CB1 protein expression. Furthermore, LPS and AEA induced PGF2a augmentation, and this was reversed by antagonizing CB1 receptor. Collectively, our results suggest that ECS may be involved in the mechanism by which infection causes preterm birth.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 71%

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

Bariani¹,

Rubio²,

Cella³

et al. 2015

Reproduction

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“…Since m-AEA was also capable of inducing NO production, we examined whether LPS-induced NO production was mediated by AEA. Our results showed that decidual and uterine LPS-induced NO production was abrogated by co-incubation with CB1 (AM251) antagonist, which suggests that AEA is mediating LPS effect [9,10] .…”

Section: Inflammatory Agents In Septic Miscarriagementioning

confidence: 57%

“…To confirm that AEA was modulating NO levels via iNOS, tissues were incubated in the presence of m-AEA plus 1,400 W (a selective iNOS inhibitor). We observed that NO production induced by m-AEA was markedly reduced by co-incubation of m-AEA with 1,400 W [9,10] . Since m-AEA was also capable of inducing NO production, we examined whether LPS-induced NO production was mediated by AEA.…”

Section: Inflammatory Agents In Septic Miscarriagementioning

confidence: 78%

Inflammatory Agents Involved in Septic Miscarriage

Aisemberg

Vercelli²,

Wolfson³

et al. 2010

Neuroimmunomodulation

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Even though the understanding of the cause of early pregnancy loss due to chromosomal abnormalities has improved, there is a dearth of knowledge of the causes of loss in euploid conceptuses. Maternal infections are a cause of abort in humans, but the mechanisms are not clear, so we have developed a murine model to study the mechanism of septic abortion by inducing embryonic resorption (ER) with lipopolysaccharide (LPS). We demonstrated that augmented production of nitric oxide (NO) and prostaglandins (PG) is involved in ER, and that inhibitors of their synthesis could prevent ER. Also, we observed an increase in the oxidative damage, evidenced by nitration of tyrosine proteins, due to the peroxynitrite anion. Since an association between chronic marijuana smoking and early miscarriage has been shown in women, we studied the participation of anandamide (AEA), the principal endocannabinoid, on the mechanism of action of LPS. We showed that LPS-induced NO synthesis and tissue damage were mediated by AEA, and that this endotoxin inhibited AEA degradation and increased its synthesis. These results suggest that several inflammatory molecules participate in the mechanism of early pregnancy loss and that their modulation could be useful tools to prevent it.

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“…In previous studies, although endocannabinoids have been reported to have the proinflammatory role in the development of inflammation under certain pathologic conditions (Vercelli et al, 2009;Gatta et al, 2012), numerous reports have shown that endocannabinoids exert anti-inflammatory action in a variety of experimental models of inflammatory disease, including experimental hepatitis (Hegde et al, 2008), inflammatory bowel disease (Di Sabatino et al, 2011), lipopolysaccharide (LPS)-induced pulmonary inflammation (Berdyshev et al, 1998), nephropathy (Mukhopadhyay et al, 2010a;Mukhopadhyay et al, 2010b), and multiple sclerosis (Mestre et al, 2005). Among endocannabinoids, anandamide (AEA) has been documented to exert anti-inflammatory effects, but it has also been considered as a source of proinflammatory factors (Gatta et al, 2012).…”

Section: Introductionmentioning

confidence: 97%

Protective Action of Anandamide and Its COX-2 Metabolite against L-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes

Xia

Abais

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Recent studies have demonstrated that L-homocysteine (Hcys)-induced podocyte injury leading to glomerular damage or sclerosis is attributable to the activation of the nucleotidebinding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome. Given the demonstrated antiinflammatory effects of endocannabinoids, the present study was designed to test whether anandamide (AEA) or its metabolites diminish NLRP3 inflammasome activation and prevent podocyte injury and associated glomerular damage during hyperhomocysteinemia (hHcys). AEA (100 mM) inhibited Hcysinduced NLRP3 inflammasome activation in cultured podocytes, as indicated by elevated caspase-1 activity and interleukin-1b levels, and attenuated podocyte dysfunction, as shown by reduced vascular endothelial growth factor production. These effects of AEA were inhibited by the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CEL). In mice in vivo, AEA treatment attenuated glomerular NLRP3 inflammasome activation induced by hHcys accompanying a folate-free diet, on the basis of inhibition of hHcys-induced colocalization of NLRP3 molecules and increased interleukin-1b levels in glomeruli. Correspondingly, AEA prevented hHcys-induced proteinuria, albuminuria, and glomerular damage observed microscopically. Hcys-and AEA-induced effects were absent in NLRP3-knockout mice. These beneficial effects of AEA against hHcys-induced NLRP3 inflammasome activation and glomerular injury were not observed in mice cotreated with CEL. We further demonstrated that prostaglandin E2-ethanolamide (PGE2-EA), a COX-2 product of AEA, at 10 mM had a similar inhibitory effect to that of 100 mM AEA on Hcys-induced NLRP3 inflammasome formation and activation in cultured podocytes. From these results, we conclude that AEA has anti-inflammatory properties, protecting podocytes from Hcys-induced injury by inhibition of NLRP3 inflammasome activation through its COX-2 metabolite, PGE2-EA.

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Anandamide regulates lipopolysaccharide-induced nitric oxide synthesis and tissue damage in the murine uterus

Cited by 27 publications

References 29 publications

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

Inflammatory Agents Involved in Septic Miscarriage

Protective Action of Anandamide and Its COX-2 Metabolite against L-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes

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