System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Ppublish 10 citations

PubMed: 37774369 DOI: 10.1182/blood.2022019282

Cold exposure induces vaso-occlusion and pain in sickle mice that depend on complement activation.

Blood 142(22):1918-1927

Authors: Zalaya K Ivy, John D Belcher, Iryna A Khasabova, Chunsheng Chen, Joseph P Juliette, Fuad Abdulla, Conglin Ruan, Kaje Allen, Julia Nguyen, Victoria M Rogness, Joan D Beckman, Sergey G Khasabov, Kalpna Gupta, Ronald P Taylor, Donald A Simone, Gregory M Vercellotti

Affiliations

  • Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN.
  • Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN.
  • Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA.
  • Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA.

Abstract

Vaso-occlusive pain episodes (VOE) cause severe pain in patients with sickle cell disease (SCD). Vaso-occlusive events promote ischemia/reperfusion pathobiology that activates complement. We hypothesized that complement activation is linked to VOE. We used cold to induce VOE in the Townes sickle homozygous for hemoglobin S (HbSS) mouse model and complement inhibitors to determine whether anaphylatoxin C5a mediates VOE. We used a dorsal skinfold chamber to measure microvascular stasis (vaso-occlusion) and von Frey filaments applied to the plantar surface of the hind paw to assess mechanical hyperalgesia in HbSS and control Townes mice homozygous for hemoglobin A (HbAA) mice after cold exposure at 10°C/50°F for 1 hour. Cold exposure induced more vaso-occlusion in nonhyperalgesic HbSS mice (33%) than in HbAA mice (11%) or HbSS mice left at room temperature (1%). Cold exposure also produced mechanical hyperalgesia as measured by paw withdrawal threshold in HbSS mice compared with that in HbAA mice or HbSS mice left at room temperature. Vaso-occlusion and hyperalgesia were associated with an increase in complement activation fragments Bb and C5a in plasma of HbSS mice after cold exposure. This was accompanied by an increase in proinflammatory NF-κB activation and VCAM-1 and ICAM-1 expression in the liver. Pretreatment of nonhyperalgesic HbSS mice before cold exposure with anti-C5 or anti-C5aR monoclonal antibodies (mAbs) decreased vaso-occlusion, mechanical hyperalgesia, complement activation, and liver inflammatory markers compared with pretreatment with control mAb. Anti-C5 or -C5aR mAb infusion also abrogated mechanical hyperalgesia in HbSS mice with ongoing hyperalgesia at baseline. These findings suggest that C5a promotes vaso-occlusion, pain, and inflammation during VOE and may play a role in chronic pain.

MeSH

Hemoglobins, Hematology, Pain, Cold Temperature, Liver, Complement System Proteins, Hyperalgesia, Complement Activation, Temperature

Cited by