BML-111, a lipoxin receptor agonist, modulates the immune response and reduces the severity of collagen-induced arthritis

Zhang, L.; Zhang, X.; Wu, Ping; Li, H.; Jin, Shudong; Zhou, Xin‐Wen; Li, Y.; Ye, D.; Chen, B.; Wan, Jinyuan

doi:10.1007/s00011-007-7141-z

Cited by 57 publications

(44 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In both models, the reduced levels of LXA 4 correlated with an increased expression of proinflammatory cytokines and increased tissue damage. Additional support for a protective role of LXA 4 during arthritis comes from a recent study demonstrating beneficial effects of an LXA 4 agonist on murine collagen-induced arthritis (29). Moreover, overexpression of 15-LO in rabbits was shown to ameliorate inflammation, tissue damage, and bone loss in a model of acute periodontitis (34).…”

Section: Discussionmentioning

confidence: 98%

12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis

Krönke

Katzenbeisser

Uderhardt

et al. 2009

The Journal of Immunology

141

View full text Add to dashboard Cite

Eicosanoids are essential mediators of the inflammatory response and contribute both to the initiation and the resolution of inflammation. Leukocyte-type 12/15-lipoxygenase (12/15-LO) represents a major enzyme involved in the generation of a subclass of eicosanoids, including the anti-inflammatory lipoxin A4 (LXA4). Nevertheless, the impact of 12/15-LO on chronic inflammatory diseases such as arthritis has remained elusive. By using two experimental models of arthritis, the K/BxN serum-transfer and a TNF transgenic mouse model, we show that deletion of 12/15-LO leads to uncontrolled inflammation and tissue damage. Consistent with these findings, 12/15-LO-deficient mice showed enhanced inflammatory gene expression and decreased levels of LXA4 within their inflamed synovia. In isolated macrophages, the addition of 12/15-LO-derived eicosanoids blocked both phosphorylation of p38MAPK and expression of a subset of proinflammatory genes. Conversely, 12/15-LO-deficient macrophages displayed significantly reduced levels of LXA4, which correlated with increased activation of p38MAPK and an enhanced inflammatory gene expression after stimulation with TNF-α. Taken together, these results support an anti-inflammatory and tissue-protective role of 12/15-LO and its products during chronic inflammatory disorders such as arthritis.

show abstract

Section: Discussionmentioning

confidence: 98%

12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis

Krönke

Katzenbeisser

Uderhardt

et al. 2009

The Journal of Immunology

141

View full text Add to dashboard Cite

show abstract

“…Interestingly lipoxins that are products of arachidonic acid, produced by the 5-LO pathway that have been shown to have anti-inflammatory activities [35] and been shown to decrease anti-collagen antibody production in the CIA model [36]. This leads to the possibility that 5-LO blockade could result decreased lipoxin levels and increased inflammation and antibody production in the model.…”

Section: Discussionmentioning

confidence: 99%

Combination therapies that inhibit cyclooxygenase-2 and leukotriene synthesis prevent disease in murine collagen induced arthritis

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Since LXA 4 is rapidly inactivated in vivo , stable analogs have been synthesized (Chiang et al., 2000). BML‐111 (5(S),6(R),7‐trihydroxyheptanoic acid methyl ester) is a commercially available LXA 4 analog and ALX receptor agonist that is a key factor in reducing inflammation and neutrophil infiltration and increasing anti‐inflammatory factors (e.g., IL‐4, IL‐10) in a number of peripheral inflammatory disorders (Conte et al., 2010; Gong et al., 2012; H. Li et al., 2014, 2008; Wang et al., 2014; Zhang et al., 2007, 2008). …”

Section: Introductionmentioning

confidence: 99%

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery

et al. 2017

View full text Add to dashboard Cite

BackgroundResolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A4 (LXA 4) is an anti‐inflammatory, pro‐resolution lipid mediator that reduces neuroinflammation in stroke. Since LXA 4 is rapidly inactivated, potent analogs have been synthesized, including BML‐111. We hypothesized that post‐ischemic, intravenous treatment with BML‐111 for 1 week would provide neuroprotection and reduce neurobehavioral deficits at 4 weeks after ischemic stroke in rats. Additionally, we investigated the potential protective mechanisms of BML‐111 on the post‐stroke molecular and cellular profile.MethodsA total of 133 male Sprague‐Dawley rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) and BML‐111 administration was started at the time of reperfusion. Two methods of week‐long BML‐111 intravenous administration were tested: continuous infusion via ALZET ® osmotic pumps (1.25 and 3.75 μg μl−1 hr−1), or freshly prepared daily single injections (0.3, 1, and 3 mg/kg). We report for the first time on the stability of BML‐111 and characterized an optimal dose and a dosing schedule for the administration of BML‐111.ResultsOne week of BML‐111 intravenous injections did not reduce infarct size or improve behavioral deficits 4 weeks after ischemic stroke. However, post‐ischemic treatment with BML‐111 did elicit early protective effects as demonstrated by a significant reduction in infarct volume and improved sensorimotor function at 1 week after stroke. This protection was associated with reduced pro‐inflammatory cytokine and chemokine levels, decreased M1 CD40+ macrophages, and increased alternatively activated, anti‐inflammatory M2 microglia/macrophage cell populations in the post‐ischemic brain.ConclusionThese data suggest that targeting the endogenous LXA 4 pathway could be a promising therapeutic strategy for the treatment of ischemic stroke. More work is necessary to determine whether a different dosing regimen or more stable LXA 4 analogs could confer long‐term protection.

show abstract

BML-111, a lipoxin receptor agonist, modulates the immune response and reduces the severity of collagen-induced arthritis

Abstract: BML-111 attenuated CIA in part by negatively regulating the immune response, which implicates the potential pharmacological value of LXs in the treatment of chronic immune-mediated inflammatory diseases such as RA.

Cited by 57 publications

References 40 publications

12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis

12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis

Combination therapies that inhibit cyclooxygenase-2 and leukotriene synthesis prevent disease in murine collagen induced arthritis

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery

Contact Info

Product

Resources

About

BML-111, a lipoxin receptor agonist, modulates the immune response and reduces the severity of collagen-induced arthritis

Abstract: BML-111 attenuated CIA in part by negatively regulating the immune response, which implicates the potential pharmacological value of LXs in the treatment of chronic immune-mediated inflammatory diseases such as RA.

Cited by 57 publications

References 40 publications

12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis

12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis

Combination therapies that inhibit cyclooxygenase-2 and leukotriene synthesis prevent disease in murine collagen induced arthritis

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

Contact Info

Product

Resources

About

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A₄ analog: Protective mechanisms and long‐term effects on neurological recovery