Articular inflammation induced by an enzymatically-inactive Lys49 phospholipase A 2 : activation of endogenous phospholipases contributes to the pronociceptive effect

Journal of venomous animals and toxins

Yara Cury³  José⁴  Sandra Coccuzzo Sampaio⁵  Anna⁶  rrez⁷  Renata Gonç⁷  Bruno Lomonte⁸  Morena Brazil Sant’⁸  alves Dias⁸  a Gutié⁸  Fernando Queiroz Cunha⁸  Marí^1,10  Gisele Picolo^1,12 

[1] , Costa Rica;Clodomiro Picado Institute, Faculty of Microbiology, University of Costa Rica, San JoséDepartment of Pharmacology, Faculty of Medicine of RibeirãDepartment of Pharmacology, Institute of Biomedical Sciences, University of SãHealthy Sciences Institute, Paulista University (UNIP), SãLaboratory of Pathophysiology, Butantan Institute, SãSpecial Laboratory of Pain and Signaling, Butantan Institute, São Paulo, Brazil;o Paulo, Ribeirão Paulo, São Preto, Brazil;o Preto, University of Sã

关键词: Lys49-PLA2;    Myotoxin II;    Arthritis;    Bothrops asper;    Phospholipase;   

DOI  :  10.1186/s40409-017-0104-0

学科分类：药理学

来源: BioMed Central

【 摘 要 】

Arthritis is a set of inflammatory conditions that induce aching, stiffness, swelling, pain and may cause functional disability with severe consequences to the patient’s lives. These are multi-mediated pathologies that cannot be effectively protected and/or treated. Therefore, the aim of this study was to establish a new model of acute arthritis, using a Lys49-PLA2 (Bothrops asper myotoxin II; MT-II) to induce articular inflammation. The articular inflammation was induced by MT-II (10 μg/joint) injection into the left tibio-tarsal or femoral-tibial-patellar joints. Cellular influx was evaluated counting total and differential cells that migrated to the joint. The plasma extravasation was determined using Evans blue dye. The edematogenic response was evaluated measuring the joint thickness using a caliper. The articular hypernociception was determined by a dorsal flexion of the tibio-tarsal joint using an electronic pressure-meter test. The mediators involved in the articular hypernociception were evaluated using receptor antagonists and enzymatic inhibitors. Plasma extravasation in the knee joints was observed 5 and 15 min after MT-II (10 μg/joint) injection. MT-II also induced a polymorphonuclear cell influx into the femoral-tibial-patellar joints observed 8 h after its injection, a period that coincided with the peak of the hyperalgesic effect. Hyperalgesia was inhibited by the pretreatment of the animals with cyclooxygenase inhibitor indomethacin, with type-2 cyclooxygenase inhibitor celecoxib, with AACOCF3 and PACOCF3, inhibitors of cytosolic and Ca2+-independent PLA2s, respectively, with bradykinin B2 receptor antagonist HOE 140, with antibodies against TNFα, IL-1β, IL-6 and CINC-1 and with selective ET-A (BQ-123) and ET-B (BQ-788) endothelin receptors antagonists. The MT-II-induced hyperalgesia was not altered by the lipoxygenase inhibitor zileuton, by the bradykinin B1 receptor antagonist Lys-(Des-Arg9,Leu8)-bradykinin, by the histamine and serotonin antagonists promethazine and methysergide, respectively, by the nitric oxide inhibitor LNMMA and by the inhibitor of matrix 1-, 2-, 3-, 8- and 9- metalloproteinases GM6001 (Ilomastat). These results demonstrated the multi-mediated characteristic of the articular inflammation induced by MT-II, which demonstrates its relevance as a model for arthritis mechanisms and treatment evaluation.

【 授权许可】

CC BY