The role of salivary histatin and the human cathelicidin LL-37 in wound healing and innate immunity

2010 ◽  
Vol 391 (5) ◽  
pp. 541-548 ◽  
Author(s):  
Menno J. Oudhoff ◽  
Marjolein E. Blaauboer ◽  
Kamran Nazmi ◽  
Nina Scheres ◽  
Jan G.M. Bolscher ◽  
...  
Keyword(s):  
Wound Healing ◽  
Innate Immunity ◽  
Antimicrobial Peptides ◽  
Wound Repair ◽  
Neutrophil Migration ◽  
Fibroblast Migration ◽  
Initial Stage ◽  
Epithelial Cell Migration ◽  
Oral Wound Healing ◽  
Multicellular Organisms

Abstract Antimicrobial peptides are multifunctional in innate immunity and wound repair of multicellular organisms. We were the first to discover that histatins, a family of salivary antimicrobial peptides, enhance epithelial cell migration, suggesting a role in oral wound healing. It is unknown whether histatins display innate-immunity activities, similar to other antimicrobial peptides such as LL-37. Therefore, we compared the effect of Histatin-2 and LL-37 on several activities within the context of wound healing and innate immunity. We found that Histatin-2 enhances fibroblast migration, but only weakly induces proliferation. LL-37 enhances both fibroblast migration and proliferation, but only at a narrow concentration optimum (approximately 1 μm). At higher concentrations LL-37 causes cell death, whereas Histatin-2 is not cytotoxic. Both peptides do not alter fibroblast-to-myofibroblast differentiation. Histatin-2 does not alter interleukin-8 (IL-8) expression and lipopolysaccharide (LPS)-elevated cytokine and chemokine expression. In contrast, LL-37 induces IL-8 expression, but dampens the LPS-induced immune response. Neither Histatin-2 nor LL-37 affects human-neutrophil migration. Histatins are, unlike other antimicrobial peptides, not cytotoxic or proinflammatory. It seems that they are important for the initial stage of wound healing in which fast wound coverage is important for healing without infection, inflammation, or fibrosis development. Interestingly, these characteristics are more typical for the mouth than for skin.

scholarly journals The interaction of ceramide 1-phosphate with group IVA cytosolic phospholipase A2 coordinates acute wound healing and repair

2019 ◽  
Vol 12 (610) ◽  
pp. eaav5918 ◽  
Author(s):  
H. Patrick MacKnight ◽  
Daniel J. Stephenson ◽  
L. Alexis Hoeferlin ◽  
Savannah D. Benusa ◽  
James T. DeLigio ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Repair ◽  
Dermal Fibroblasts ◽  
Mutant Form ◽  
Collagen Deposition ◽  
Wild Type ◽  
Fibroblast Migration ◽  
Cytosolic Phospholipase ◽  
Group Iva ◽  
Ceramide 1

The sphingolipid ceramide 1-phosphate (C1P) directly binds to and activates group IVA cytosolic phospholipase A2 (cPLA2α) to stimulate the production of eicosanoids. Because eicosanoids are important in wound healing, we examined the repair of skin wounds in knockout (KO) mice lacking cPLA2α and in knock-in (KI) mice in which endogenous cPLA2α was replaced with a mutant form having an ablated C1P interaction site. Wound closure rate was not affected in the KO or KI mice, but wound maturation was enhanced in the KI mice compared to that in wild-type controls. Wounds in KI mice displayed increased infiltration of dermal fibroblasts into the wound environment, increased wound tensile strength, and a higher ratio of type I:type III collagen. In vitro, primary dermal fibroblasts (pDFs) from KI mice showed substantially increased collagen deposition and migration velocity compared to pDFs from wild-type and KO mice. KI mice also showed an altered eicosanoid profile of reduced proinflammatory prostaglandins (PGE2 and TXB2) and an increased abundance of certain hydroxyeicosatetraenoic acid (HETE) species. Specifically, an increase in 5-HETE enhanced dermal fibroblast migration and collagen deposition. This gain-of-function role for the mutant cPLA2α was also linked to the relocalization of cPLA2α and 5-HETE biosynthetic enzymes to the cytoplasm and cytoplasmic vesicles. These findings demonstrate the regulation of key wound-healing mechanisms in vivo by a defined protein-lipid interaction and provide insights into the roles that cPLA2α and eicosanoids play in orchestrating wound repair.

scholarly journals Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing

2020 ◽  
Vol 117 (17) ◽  
pp. 9477-9482 ◽  
Author(s):  
Miguel Quiros ◽  
Darius Feier ◽  
Dorothee Birkl ◽  
Rachit Agarwal ◽  
Dennis W. Zhou ◽  
...  
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Epithelial Cell ◽  
Wound Repair ◽  
Intestinal Epithelial Cell ◽  
Intestinal Inflammation ◽  
Small Gtpase ◽  
Intestinal Epithelial ◽  
Epithelial Cell Migration ◽  
Cell Migration And Proliferation

Resolution of intestinal inflammation and wound repair are active processes that mediate epithelial healing at mucosal surfaces. Lipid molecules referred to as specialized proresolving mediators (SPMs) play an important role in the restorative response. Resolvin E1 (RvE1), a SPM derived from omega-3 fatty acids, has been reported to dampen intestinal inflammation by promoting anti-inflammatory responses including increased neutrophil spherocytosis and macrophage production of IL-10. Despite these observations, a role for RvE1 in regulating intestinal epithelial cell migration and proliferation during mucosal wound repair has not been explored. Using an endoscopic biopsy-based wound healing model, we report that RvE1 is locally produced in response to intestinal mucosal injury. Exposure of intestinal epithelial cells to RvE1 promoted wound repair by increasing cellular proliferation and migration through activation of signaling pathways including CREB, mTOR, and Src-FAK. Additionally, RvE1-triggered activation of the small GTPase Rac1 led to increased intracellular reactive oxygen species (ROS) production, cell–matrix adhesion, and cellular protrusions at the leading edge of migrating cells. Furthermore, in situ administration of RvE1-encapsulated synthetic targeted polymeric nanoparticles into intestinal wounds promoted mucosal repair. Together, these findings demonstrate that RvE1 functions as a prorepair lipid mediator by increasing intestinal epithelial cell migration and proliferation, and highlight potential therapeutic applications for this SPM to promote mucosal healing in the intestine.

scholarly journals Cloning, Expression and Effects of P. americana Thymosin on Wound Healing

2019 ◽  
Vol 20 (19) ◽  
pp. 4932 ◽  
Author(s):  
Jie Jing ◽  
Xiaohong Sun ◽  
Chuang Zhou ◽  
Yifan Zhang ◽  
Yongmei Shen ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factors ◽  
Tissue Regeneration ◽  
Dna Sequences ◽  
Wound Repair ◽  
Periplaneta Americana ◽  
American Cockroach ◽  
Promote Wound Healing ◽  
Fibroblast Migration

The American cockroach (Periplaneta americana) is a medicinal insect. Its extract is used clinically to promote wound healing and tissue regeneration, but the effective medicinal components and mechanisms are not yet clear. It has been reported that human thymosin beta 4 (Tβ4) may accelerate skin wound healing, however, the role of P. americana thymosin (Pa-THYs) is still poorly understood. In the present study, we identify and analyze the DNA sequences of Pa-THYs by bioinformatics analysis. Then we clone, express, and purify the Pa-THYs proteins and evaluate the activity of recombinant Pa-THYs proteins by cell migration and proliferation assays in NIH/3T3 cells. To elucidate the role of Pa-THYs in wound healing, a mouse model is established, and we evaluate wound contraction, histopathological parameters, and the expressions of several key growth factors after Pa-THYs treatment. Our results showed that three THY variants were formed by skipping splicing of exons. Pa-THYs could promote fibroblast migration, but have no effect on fibroblast proliferation. In wound repair, Pa-THYs proteins could effectively promote wound healing through stimulating dermal tissue regeneration, angiogenesis, and collagen deposition. On the molecular mechanism, Pa-THYs also stimulated the expression of several key growth factors to promote wound healing. The data suggest that Pa-THYs could be a potential drug for promoting wound repair.

Aberrant mucosal wound repair in the absence of secretory leukocyte protease inhibitor

2004 ◽  
Vol 92 (08) ◽  
pp. 288-297 ◽  
Author(s):  
Moon-Jin Jeong ◽  
Salvador Nares ◽  
Gillian Ashcroft ◽  
Nikola Angelov ◽  
Niki Moutsopoulos ◽  
...  
Keyword(s):  
Wound Healing ◽  
Protease Inhibitor ◽  
Wound Repair ◽  
Molecular Mechanisms ◽  
Secretory Leukocyte Protease Inhibitor ◽  
Matrix Deposition ◽  
Wound Model ◽  
Novel Approach ◽  
Oral Wound Healing

SummarySecretory leukocyte protease inhibitor (SLPI) is a cationic serine protease inhibitor with anti-microbial and anti-inflammatory properties found in large quantities in mucosal fluids, including saliva. SLPI is expressed during cutaneous wound healing, however, its role in oral wound repair is unknown. We have used a novel approach involving a murine buccal mucosal acute wound model to investigate the role of SLPI in oral healing. In parallel to the observed cutaneous healing phenotype, an absence of SLPI results in markedly impaired oral wound healing associated with increased inflammation and raised elastase activity. Moreover, matrix deposition was decreased, while MMP activity was enhanced in the oral SLPI null wounds suggesting deregulated proteolysis. Intriguingly, regardless of genotype, reduced collagen deposition was observed in oral compared to dermal wounds, associated with reduced TGF-β expression and decreased fibroblast collagen expression in vitro. We propose that SLPI is a pivotal endogenous factor necessary for optimal tissue repair including intra-oral wound healing. In addition, our model provides a unique opportunity to delineate the cellular and molecular mechanisms underlying the differences between dermal scarring and oral scar-free healing.

scholarly journals JNK-mediated Slit-Robo signaling facilitates epithelial wound repair by extruding dying cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chiaki Iida ◽  
Shizue Ohsawa ◽  
Kiichiro Taniguchi ◽  
Masatoshi Yamamoto ◽  
Ginés Morata ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factors ◽  
Wound Repair ◽  
Physical Injury ◽  
Biological Processes ◽  
Jnk Signaling ◽  
Evolutionarily Conserved ◽  
Growth Factor Genes ◽  
Multicellular Organisms ◽  
Dying Cells

AbstractMulticellular organisms repair injured epithelium by evolutionarily conserved biological processes including activation of c-Jun N-terminal kinase (JNK) signaling. Here, we show in Drosophila imaginal epithelium that physical injury leads to the emergence of dying cells, which are extruded from the wounded tissue by JNK-induced Slit-Roundabout2 (Robo2) repulsive signaling. Reducing Slit-Robo2 signaling in the wounded tissue suppresses extrusion of dying cells and generates aberrant cells with highly upregulated growth factors Wingless (Wg) and Decapentaplegic (Dpp). The inappropriately elevated Wg and Dpp impairs wound repair, as halving one of these growth factor genes cancelled wound healing defects caused by Slit-Robo2 downregulation. Our data suggest that JNK-mediated Slit-Robo2 signaling contributes to epithelial wound repair by promoting extrusion of dying cells from the wounded tissue, which facilitates transient and appropriate induction of growth factors for proper wound healing.

scholarly journals In VitroVitamin K3Effect on Conjunctival Fibroblast Migration and Proliferation

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
I. Pinilla ◽  
L. B. Izaguirre ◽  
F. J. Gonzalvo ◽  
E. Piazuelo ◽  
M. A. Garcia-Gonzalez ◽  
...  
Keyword(s):  
Wound Healing ◽  
Vitamin K ◽  
Wound Repair ◽  
Dose Effect ◽  
Initial Time ◽  
Thymidine Uptake ◽  
Cellular Toxicity ◽  
Fibroblast Migration ◽  
Higher Doses

Purpose. To evaluate the dose effect of vitamin K3on wound healing mechanisms.Methods. Conjunctival fibroblasts were incubated for 24 hours. An artificial wound was made and the cells were incubated with fresh medium plus doses of vitamin K3to be tested. Wound repair was monitored at 0, 18, 24, and 48 hours. Proliferation was measured in actively dividing cells by [3H]thymidine uptake. Six different groups were tested: group 1/no drugs added, group 2/ethanol 0.1%, group 3/vitamin K31 mg/L, group 4/vitamin K32 mg/L, group 5/vitamin K34 mg/L, and group 6/vitamin K36 mg/L. Each experiment was carried out in triplicate and 4 times.Results. There were no differences among groups at the initial time.In vitrowound repair was slower in groups 4, 5, and 6. There were no differences between control and ethanol groups and between control and vitamin K31 mg/L groups. Fibroblast mitogenic activity was statistically decreased in all vitamin K groups; statistical differences were found among vitamin K31 mg/mL and higher doses too. In groups 5 and 6, cellular toxicity was presented.Conclusions. Vitamin K3is able to inhibit fibroblast proliferation. Vitamin K32 mg/L or higher doses inhibit wound healing repair, exhibiting cellular toxicity at 4 and 6 mg/L.

scholarly journals Cytocompatibility Properties of an Herbal Compound Solution Support In vitro Wound Healing

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Zhou ◽  
Vanessa Chrepa ◽  
Ioannis Karoussis ◽  
Michael A. Pikos ◽  
Georgios A. Kotsakis
Keyword(s):  
Wound Healing ◽  
Herbal Extract ◽  
Active Comparator ◽  
Cellular Models ◽  
Fibroblast Migration ◽  
Oral Rinse ◽  
Apical Papilla ◽  
Oral Stem Cells ◽  
Oral Wound Healing

The aim of this study was to evaluate the cytocompatibility of an herbal extract compound oral rinse [StellaLife VEGA (SLife)] against relevant human cellular models of oral surgical wound healing. SL was compared to the gold standard for peri-/post-operative oral surgical use, i.e., Chlorhexidine (CHX) and to a commonly utilized essential-oil (EO) based antiseptic rinse. Fibroblasts and primary oral stem cells of the apical papilla (SCAPs) were employed to assess its comparative cytotoxicity to the active comparator antiseptic rinses and its effects on wound healing in vitro. In cytotoxicity assays, multiple timepoints were tested ranging from clinically relevant of 60-s rinsing to protracted challenge of up to 5 min, to determine dose-dependent toxicity. The SLife group consistently demonstrated minimal cytotoxicity as compared to active comparators across experimental timepoints and different cells lines. At concentrations up to 20% v/v SLife-challenged fibroblasts and SCAPs demonstrated no significant toxicity as compared to unstimulated controls (p > 0.05). When assessing wound healing, a scratch wound assay revealed significantly accelerated cell migration for SLife as compared to CHX (p < 0.05). Notably, all active comparator antiseptic rinses affected wound healing responses by significantly reducing total collagen deposition after intermittent “rinsing” intervals that simulated post-surgical oral rinsing. Nonetheless, intermittent as well as continuous challenge of cells with SLife had a positive effect in functional collagen assays. An herbal extract compound-based oral rinse was found to be cytocompatible to cells critical to oral wound healing and to promote fibroblast migration and differentiation, contrary to existing antiseptic rinses that lack selective cytotoxicity.

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