High Heme and Low Heme Oxygenase-1 Are Associated with Mast Cell Activation/Degranulation in HIV-Induced Chronic Widespread Pain
Tanima Chatterjee,
Itika Arora,
Lilly Underwood,
Anastasiia Gryshyna,
Terry L. Lewis,
Juan Xavier Masjoan Juncos,
Burel R. Goodin,
Sonya Heath,
Saurabh Aggarwal
Affiliations
Tanima Chatterjee
Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Itika Arora
Division of Developmental Biology and the Reproductive Sciences Center, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USA
Lilly Underwood
Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Anastasiia Gryshyna
Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Terry L. Lewis
Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Juan Xavier Masjoan Juncos
Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Burel R. Goodin
Washington University Pain Center, Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO 98105, USA
Sonya Heath
Division of Infectious Disease, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Saurabh Aggarwal
Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
An overwhelming number of people with HIV (PWH) experience chronic widespread pain (CWP) throughout their lifetimes. Previously, we demonstrated that PWH with CWP have increased hemolysis and attenuated heme oxygenase 1 (HO-1) levels. HO-1 degrades reactive, cell-free heme into antioxidants like biliverdin and carbon monoxide (CO). We found that high heme or low HO-1 caused hyperalgesia in animals, likely through multiple mechanisms. In this study, we hypothesized that high heme or low HO-1 caused mast cell activation/degranulation, resulting in the release of pain mediators like histamine and bradykinin. PWH who self-report CWP were recruited from the University of Alabama at Birmingham HIV clinic. Animal models included HO-1−/− mice and hemolytic mice, where C57BL/6 mice were injected intraperitoneally with phenylhydrazine hydrochloride (PHZ). Results demonstrated that plasma histamine and bradykinin were elevated in PWH with CWP. These pain mediators were also high in HO-1−/− mice and in hemolytic mice. Both in vivo and in vitro (RBL-2H3 mast cells), heme-induced mast cell degranulation was inhibited by treatment with CORM-A1, a CO donor. CORM-A1 also attenuated mechanical and thermal (cold) allodynia in hemolytic mice. Together, the data suggest that mast cell activation secondary to high heme or low HO-1 seen in cells and animals correlates with elevated plasma levels of heme, histamine, and bradykinin in PWH with CWP.
