Mast cell activation contributes to sickle cell pathobiology and pain in mice

Lucile Vincent, Derek Vang, Julia Nguyen, Mihir Gupta, Kathryn Luk, Marna E Ericson, Donald A Simone, Kalpna Gupta

Research output: Contribution to journalArticle

91 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1853-1862
Number of pages10
JournalBlood
Volume122
Issue number11
DOIs
StatePublished - Jan 1 2013

Fingerprint

Mast Cells
Chemical activation
Pain
Morphine
Skin
Sickle Cell Anemia
Cromolyn Sodium
Biopsy
Hyperalgesia
Granulocyte-Macrophage Colony-Stimulating Factor
Substance P
Blood
Cells
Neurogenic Inflammation
Cytokines
Cell Degranulation
Nociceptors
Spinal Ganglia
Analgesia
Transgenic Mice

Cite this

Vincent, L., Vang, D., Nguyen, J., Gupta, M., Luk, K., Ericson, M. E., ... Gupta, K. (2013). Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood, 122(11), 1853-1862. https://doi.org/10.1182/blood-2013-04-498105

Mast cell activation contributes to sickle cell pathobiology and pain in mice. / Vincent, Lucile; Vang, Derek; Nguyen, Julia; Gupta, Mihir; Luk, Kathryn; Ericson, Marna E; Simone, Donald A; Gupta, Kalpna.

In: Blood, Vol. 122, No. 11, 01.01.2013, p. 1853-1862.

Research output: Contribution to journalArticle

Vincent, L, Vang, D, Nguyen, J, Gupta, M, Luk, K, Ericson, ME, Simone, DA & Gupta, K 2013, 'Mast cell activation contributes to sickle cell pathobiology and pain in mice', Blood, vol. 122, no. 11, pp. 1853-1862. https://doi.org/10.1182/blood-2013-04-498105
Vincent, Lucile ; Vang, Derek ; Nguyen, Julia ; Gupta, Mihir ; Luk, Kathryn ; Ericson, Marna E ; Simone, Donald A ; Gupta, Kalpna. / Mast cell activation contributes to sickle cell pathobiology and pain in mice. In: Blood. 2013 ; Vol. 122, No. 11. pp. 1853-1862.
@article{454894b187d4452dbf34c570f833131a,
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.",
author = "Lucile Vincent and Derek Vang and Julia Nguyen and Mihir Gupta and Kathryn Luk and Ericson, {Marna E} and Simone, {Donald A} and Kalpna Gupta",
year = "2013",
month = "1",
day = "1",
doi = "10.1182/blood-2013-04-498105",
language = "English (US)",
volume = "122",
pages = "1853--1862",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "11",

}

TY - JOUR

T1 - Mast cell activation contributes to sickle cell pathobiology and pain in mice

AU - Vincent, Lucile

AU - Vang, Derek

AU - Nguyen, Julia

AU - Gupta, Mihir

AU - Luk, Kathryn

AU - Ericson, Marna E

AU - Simone, Donald A

AU - Gupta, Kalpna

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84887331111&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887331111&partnerID=8YFLogxK

U2 - 10.1182/blood-2013-04-498105

DO - 10.1182/blood-2013-04-498105

M3 - Article

VL - 122

SP - 1853

EP - 1862

JO - Blood

JF - Blood

SN - 0006-4971

IS - 11

ER -