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: De-Yong Liang, XiangQi Li, Wen-Wu Li, Dennis Fiorino, Yanli Qiao, Peyman Sahbaie, David C Yeomans, J David Clark
• Journal: Anesthesiology (Anesthesiology) Vol. 113 Issue 4 Pg. 945-56 (Oct 2010) ISSN: 1528-1175 [Electronic] United States
• PMID: 20823759 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Biomarkers
• Caspase Inhibitors
• Ccl3 protein, mouse
• Chemokine CCL3
• Interleukin-1beta
• Granulocyte Colony-Stimulating Factor
• Caspase 1
• Dinoprostone

Topics

• Animals
• Biomarkers
• Body Temperature (drug effects)
• Caspase 1 (physiology)
• Caspase Inhibitors
• Chemokine CCL3 (metabolism)
• Dinoprostone (metabolism)
• Edema (pathology)
• Granulocyte Colony-Stimulating Factor (cerebrospinal fluid)
• Hindlimb (pathology)
• Hot Temperature
• Hyperalgesia (physiopathology)
• Immunohistochemistry
• Inflammation (metabolism, pathology)
• Interleukin-1beta (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Pain (psychology)
• Pain Measurement
• Pain Threshold (physiology)
• Skin (metabolism)
• Surgical Procedures, Operative (adverse effects)