Broad-Spectrum Inhibition of the CC-Chemokine Class Improves Wound Healing and Wound Angiogenesis

Abstract

Angiogenesis is involved in the inflammation and proliferation stages of wound healing, to bring inflammatory cells to the wound and provide a microvascular network to maintain new tissue formation. An excess of inflammation, however, leads to prolonged wound healing and scar formation, often resulting in unfavourable outcomes such as amputation. CC-chemokines play key roles in the promotion of inflammation and inflammatory-driven angiogenesis. Therefore, inhibition of the CC-chemokine class may improve wound healing. We aimed to determine if the broad-spectrum CC-chemokine inhibitor “35K” could accelerate wound healing in vivo in mice. In a murine wound healing model, 35K protein or phosphate buffered saline (PBS, control) were added topically daily to wounds. Cohorts of mice were assessed in the early stages (four days post-wounding) and in the later stages of wound repair (10 and 21 days post-wounding). Topical application of the 35K protein inhibited CC-chemokine expression (CCL5, CCL2) in wounds and caused enhanced blood flow recovery and wound closure in early-mid stage wounds. In addition, 35K promoted neovascularisation in the early stages of wound repair. Furthermore, 35K treated wounds had significantly lower expression of the p65 subunit of NF-κB, a key inflammatory transcription factor, and augmented wound expression of the pro-angiogenic and pro-repair cytokine TGF-β. These findings show that broad-spectrum CC-chemokine inhibition may be beneficial for the promotion of wound healing.

Activation of cGMP/PKG/p65 signaling associated with PDE5‐Is downregulates CCL5 secretion by CD8+ T cells in benign prostatic hyperplasia

“…To further investigate the molecular mechanism underlying CCL5 secretion by CD8 + T cells in low androgen conditions, we focused on the signaling cascade downstream of cGMP/PKG. Several studies indicated that NF‐κB plays an important regulatory role in the immune response, and that cGMP/PKG activation inhibited NF‐κB in hyperthermia‐exposed MCF‐7 cells, resulting in apoptosis . In this study, we showed, for the first time, that the cGMP/PKG pathway regulates the function of CD8 + T cells by controlling NF‐κB p65 phosphorylation, which affects the secretion of CCL5.…”

“…NF‐κB is a transcription factor playing a key role in inflammation, and several studies have demonstrated that it is regulated by the NO/cGMP/PKG signaling pathway . Therefore, we analyzed the phosphorylation of NF‐κB p65 subunit in the nuclear fraction of Molt‐3 cells treated with tadalafil/Sp‐8‐Br‐PET‐cGMP by Western blot analysis, which revealed that phospho‐NF‐κB p65 was downregulated by the drugs, but PKG inhibitor KT5823 (100 nM) reversed the effect (Figure ).…”

The discovery and development of topical medicines for wound healing

“…It is well established that prolonged inflammation and production of pro-inflammatory chemokines can lead to nonhealing wounds, and broad-spectrum chemokine inhibitors are therefore tried to limit wound inflammation. The chemokine inhibitor 35K, which inhibits the entire class of CC-chemokines, enhanced wound closure and neovascularization in murine wounds [81]. How this approach influence on wound infections needs to be further established.…”

Photobiomodulation in the Metabolism of Lipopolysaccharides‐exposed Epithelial Cells and Gingival Fibroblasts

“…In a recent study by Ridiandries et al . , topical application of the broad‐spectrum CC chemokine inhibitor was found to decrease wound CCL5 and CCL2 protein levels, leading to improved wound healing and neovascularization during the early stages, demonstrating thus the importance of the modulation of these chemokines in the tissues. In this study, wounds treated with this inhibitor showed significantly lower expression of the p65 subunit of NF‐ κ B, an important inflammatory transcription factor for increased expression of the pro‐angiogenic and prorepair cytokine TGF‐ β in the wound, demonstrating that inhibition of CC chemokines may be beneficial for the induction of wound healing.…”