title: Caspase-1 modulates incisional sensitization and inflammation.
abstract: BACKGROUND
  Surgical injury induces production and release of inflammatory mediators in the vicinity of the wound. They in turn trigger nociceptive signaling to produce hyperalgesia and pain. Interleukin-1β plays a crucial role in this process. The mechanism regulating production of this cytokine after incision is, however, unknown. Caspase-1 is a key enzyme that cleaves prointerleukin-1β to its active form. We hypothesized that caspase-1 is a crucial regulator of incisional interleukin-1β levels, nociceptive sensitization, and inflammation.
  
  
  METHODS
  These studies employed a mouse hind paw incisional model. Caspase-1 was blocked using the selective inhibitors Ac-YVAD-CMK and VRTXSD727. Nociceptive sensitization, edema, and hind paw warmth were followed in intact animals whereas caspase-1 activity, cytokine, and prostaglandin E2 levels were assessed in homogenized skin. Confocal microscopy was used to detect the expression of caspase-1 near the wounds.
  
  
  RESULTS
  Analysis of enzyme activity demonstrated that caspase-1 activity was significantly increased in periincisional skin. Pretreatment with Ac-YVAD-CMK significantly reduced mechanical allodynia and thermal hyperalgesia. Repeated administration of this inhibitor produced robust analgesia, especially to mechanical stimulation. Administration of VRTXSD727 provided qualitatively similar results. Caspase-1 inhibition also reduced edema and the normally observed increase in paw warmth around the wound site. Correspondingly, caspase-1 inhibition significantly reduced interleukin-1β as well as macrophage-inflammatory protein 1α, granulocyte colony-stimulating factor, and prostaglandin E2 levels near the wound. The expression of caspase-1 was primarily observed in keratinocytes in the epidermal layer and in neutrophils deeper in the wounds.
  
  
  CONCLUSIONS
  The current study demonstrates that the inhibition of caspase-1 reduces postsurgical sensitization and inflammation, likely through a caspase-1/interleukin-1β-dependent mechanism.
authors.affiliation: Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Liang
authors.forename: XiangQi
authors.initials: X
authors.lastname: Li
authors.forename: Wen-Wu
authors.initials: WW
authors.lastname: Li
authors.forename: Dennis
authors.initials: D
authors.lastname: Fiorino
authors.forename: Yanli
authors.initials: Y
authors.lastname: Qiao
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.forename: David C
authors.initials: DC
authors.lastname: Yeomans
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000818:Animals; D015415:Biomarkers; D001831:Body Temperature / Q000187:drug effects; D020170:Caspase 1 / Q000502:physiology*; D061945:Caspase Inhibitors; D054405:Chemokine CCL3 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000473:pathology; D016179:Granulocyte Colony-Stimulating Factor / Q000134:cerebrospinal fluid; D006614:Hindlimb / Q000473:pathology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010146:Pain / Q000523:psychology; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D012867:Skin / Q000378:metabolism; D013514:Surgical Procedures, Operative / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D061945:Caspase Inhibitors; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D053583:Interleukin-1beta; D016179:Granulocyte Colony-Stimulating Factor; D020170:Caspase 1; D015232:Dinoprostone
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