title: Mast cell activation contributes to sickle cell pathobiology and pain in mice.
abstract: Sickle cell anemia (SCA) is an inherited disorder associated with severe lifelong pain and significant morbidity. The mechanisms of pain in SCA remain poorly understood. We show that mast cell activation/degranulation contributes to sickle pain pathophysiology by promoting neurogenic inflammation and nociceptor activation via the release of substance P in the skin and dorsal root ganglion. Mast cell inhibition with imatinib ameliorated cytokine release from skin biopsies and led to a correlative decrease in granulocyte-macrophage colony-stimulating factor and white blood cells in transgenic sickle mice. Targeting mast cells by genetic mutation or pharmacologic inhibition with imatinib ameliorates tonic hyperalgesia and prevents hypoxia/reoxygenation-induced hyperalgesia in sickle mice. Pretreatment with the mast cell stabilizer cromolyn sodium improved analgesia following low doses of morphine that were otherwise ineffective. Mast cell activation therefore underlies sickle pathophysiology leading to inflammation, vascular dysfunction, pain, and requirement for high doses of morphine. Pharmacological targeting of mast cells with imatinib may be a suitable approach to address pain and perhaps treat SCA.
authors.affiliation: Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN;
authors.forename: Lucile
authors.initials: L
authors.lastname: Vincent
authors.forename: Derek
authors.initials: D
authors.lastname: Vang
authors.forename: Julia
authors.initials: J
authors.lastname: Nguyen
authors.forename: Mihir
authors.initials: M
authors.lastname: Gupta
authors.forename: Kathryn
authors.initials: K
authors.lastname: Luk
authors.forename: Marna E
authors.initials: ME
authors.lastname: Ericson
authors.forename: Donald A
authors.initials: DA
authors.lastname: Simone
authors.forename: Kalpna
authors.initials: K
authors.lastname: Gupta
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D000068877:Imatinib Mesylate; D007958:Leukocyte Count; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020078:Neurogenic Inflammation / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010146:Pain / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013373:Substance P / Q000378:metabolism
chemical_list: D001549:Benzamides; D016207:Cytokines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013373:Substance P; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000068877:Imatinib Mesylate