Caspase-1 modulates incisional sensitization and inflammation.
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.
Liang
De-Yong
DY
Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
Li
XiangQi
X
Li
Wen-Wu
WW
Fiorino
Dennis
D
Qiao
Yanli
Y
Sahbaie
Peyman
P
Yeomans
David C
DC
Clark
J David
JD
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*
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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