Host defense peptides in wound healing

Host defense peptides are effector molecules of the innate immune system. They show broad antimicrobial action against gram-positive and -negative bacteria, and they likely play a key role in activating and mediating the innate as well as adaptive immune response in infection and inflammation. These features make them of high interest for wound healing research. Non-healing and infected wounds are a major problem in patient care and health care spending. Increasing infection rates, growing bacterial resistance to common antibiotics, and the lack of effective therapeutic options for the treatment of problematic wounds emphasize the need for new approaches in therapy and pathophysiologic understanding. This review focuses on the current knowledge of host defense peptides affecting wound healing and infection. We discuss the current data and highlight the potential future developments in this field of research.     

Efficacy of the designer antimicrobial peptide SHAP1 in wound healing and wound infection

Infected wounds cause delay in wound closure and impose significantly negative effects on patient care and recovery. Antimicrobial peptides (AMPs) with antimicrobial and wound closure activities, along with little opportunity for the development of resistance, represent one of the promising agents for new therapeutic approaches in the infected wound treatment. However, therapeutic applications of these AMPs are limited by their toxicity and low stability in vivo. Previously, we reported that the 19-amino-acid designer peptide SHAP1 possessed salt-resistant antimicrobial activities. Here, we analyzed the wound closure activities of SHAP1 both in vitro and in vivo. SHAP1 did not affect the viability of human erythrocytes and keratinocytes up to 200 μM, and was not digested by exposure to proteases in the wound fluid, such as human neutrophil elastase and Staphylococcus aureus V8 proteinase for up to 12 h. SHAP1 elicited stronger wound closure activity than human cathelicidin AMP LL-37 in vitro by inducing HaCaT cell migration, which was shown to progress via transactivation of the epidermal growth factor receptor. In vivo analysis revealed that SHAP1 treatment accelerated closure and healing of full-thickness excisional wounds in mice. Moreover, SHAP1 effectively countered S. aureus infection and enhanced wound healing in S. aureus-infected murine wounds. Overall, these results suggest that SHAP1 might be developed as a novel topical agent for the infected wound treatment.     

Rhinovirus infection induces cytotoxicity and delays wound healing in bronchial epithelial cells

Background

Human rhinoviruses (RV), the most common triggers of acute asthma exacerbations, are considered not cytotoxic to the bronchial epithelium. Recent observations, however, have questioned this knowledge. The aim of this study was to evaluate the ability of RV to induce epithelial cytotoxicity and affect epithelial repair in-vitro.

Methods

Monolayers of BEAS-2B bronchial epithelial cells, seeded at different densities were exposed to RV serotypes 1b, 5, 7, 9, 14, 16. Cytotoxicity was assessed chromatometrically. Epithelial monolayers were mechanically wounded, exposed or not to RV and the repopulation of the damaged area was assessed by image analysis. Finally epithelial cell proliferation was assessed by quantitation of proliferating cell nuclear antigen (PCNA) by flow cytometry.

Results

RV1b, RV5, RV7, RV14 and RV16 were able to induce considerable epithelial cytotoxicity, more pronounced in less dense cultures, in a cell-density and dose-dependent manner. RV9 was not cytotoxic. Furthermore, RV infection diminished the self-repair capacity of bronchial epithelial cells and reduced cell proliferation.

Conclusion

RV-induced epithelial cytotoxicity may become considerable in already compromised epithelium, such as in the case of asthma. The RV-induced impairment on epithelial proliferation and self-repair capacity may contribute to the development of airway remodeling.     

Fibronectin and wound healing

I have tried to briefly review the evidence (summarized in Table II) indicating that fibronectin is important in cutaneous wound healing. Fibronectin appears to be an important factor throughout this process. It promotes the spreading of platelets at the site of injury, the adhesion and migration of neutrophils, monocytes, fibroblasts, and endothelial cells into the wound region, and the migration of epidermal cells through the granulation tissue. At the level of matrix synthesis, fibronectin appears to be involved both in the organization of the granulation tissue and basement membrane. In terms of tissue remodeling, fibronectin functions as a nonimmune opsonin for phagocytosis of debris by fibroblasts, keratinocytes, and under some circumstances, macrophages. Fibronectin also enhances the phagocytosis of immune-opsonized particles by monocytes, but whether this includes phagocytosis of bacteria remains to be determined. In general, phagocytosis of bacteria has not appeared to involve fibronectin. On the contrary, the presence of fibronectin in the wound bed may promote bacterial attachment and infection. Because of the ease of experimental manipulations, wound healing experiments have been carried out on skin more frequently than other tissues. As a result, the possible role of fibronectin has not been investigated thoroughly in the repair of internal organs and tissues. Nevertheless, it seems reasonable to speculate that fibronectin plays a central role in all wound healing situations. Finally, the wound healing problems of patients with severe factor XIII deficiencies may occur because of their inability to incorporate fibronectin into blood clots.     

瘦素与创伤愈合

瘦素作为一种多靶器官、多功能的生长因子,它在机体中具有广泛的生理作用。瘦素可能是一种新的促创伤愈合因子,它参与了创伤愈合进程的调节,腹膜内注射瘦素或局部涂抹瘦素加速了动物伤口愈合的速度。本文主要综述了近年来瘦素促进伤口愈合作用的研究现状,并从瘦素在伤口愈合过程中对上皮再生、胶原合成、血管生成、炎症反应等几方面的作用,探讨了瘦素通过调控其它促创伤愈合因子的生成及活性来发挥促伤口愈合作用的机制与途径。     

巨噬细胞与创伤愈合

巨噬细胞是创伤愈合过程中一系列复杂反应中的关键环节,它调节成纤维细胞和血管内皮细胞的生物学活性,在创伤愈合过程中占有不可替代的作用。加强巨噬细胞功能和应用细胞因匀能有效地促进创伤愈合。     

A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense

The surface of the eye actively suppresses inflammation while maintaining a remarkable capacity for epithelial wound repair. Our understanding of mechanisms that balance inflammatory/reparative responses to provide effective host defense while preserving tissue function is limited, in particular, in the cornea. Lipoxin A(4) (LXA(4)) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1) are lipid autacoids formed by 12/15-lipoxygenase (LOX) pathways that exhibit anti-inflammatory and neuroprotective properties. Here, we demonstrate that mouse corneas generate endogenous LXA(4) and NPD1. 12/15-LOX (Alox15) and LXA(4) receptor mRNA expression as well as LXA(4) formation were abrogated by epithelial removal and restored during wound healing. Amplification of these pathways by topical treatment with LXA(4) or NPD1 (1 microg) increased the rate of re-epithelialization (65-90%, n = 6-10, p < 0.03) and attenuated the sequelae of thermal injury. In contrast, the proinflammatory eicosanoids, LTB(4) and 12R-hydroxyeicosatrienoic acid, had no impact on corneal re-epithelialization. Epithelial removal induced a temporally defined influx of neutrophils into the stroma as well as formation of the proinflammatory chemokine KC. Topical treatment with LXA(4) and NPD1 significantly increased PMNs in the cornea while abrogating KC formation by 60%. More importantly, Alox15-deficient mice exhibited a defect in both corneal re-epithelialization and neutrophil recruitment that correlated with a 43% reduction in endogenous LXA(4) formation. Collectively, these results identify a novel action for the mouse 12/15-LOX (Alox15) and its products, LXA(4) and NPD1, in wound healing that is distinct from their well established anti-inflammatory properties.     

Stress and wound healing.

An experiment was performed to compare the effects of stressors--cold, heat and noise--on primary wound activity (i.e., wound closure in the first 24 h after wound infliction) and on rate of healing in mice. A significant correlation was found between reduced primary wound activity and a faster rate of healing. Conversely, a correlation was found between relatively greater primary wound activity and a slower rate of healing. A possible explanation of this correlation is a compensatory mechanism inherent to the skin healing process. This mechanism is visualized as (1) stress exposure affecting the skin by (a) causing it to become thinner and tauter and (b) causing it to have less elastic recoil; therefore, (2) when a square wound is produced in stressed skin, (a) the wound does not recoil readily or gapes soon after cutting and (b) a longer wound perimeter results. Because there is evidence that rate of healing is governed by cells on the wound perimeter, the greater the perimeter, the greater the number of cells that will undergo rapid mitosis and the faster will be the rate of healing. Therefore, stressed skin will heal at a faster rate, compensating for the loss of elasticity and cellular depletion caused by stress. This study is of interest to anthropology because it deals with dynamic adaptation, trying to grasp the meaning of the elusive endocrine interface between environmental stimulation and a measurable physical entity like healing. This work may have revealed a functional complex that is common to the healing of all mammalian skin, whereby retarding effects of stress on the healing process are obviated.     

Redox signals in wound healing

Physical trauma represents one of the most primitive challenges that threatened survival. Healing a problem wound requires a multi-faceted comprehensive approach. First and foremost, the wound environment will have to be made receptive to therapies. Second, the appropriate therapeutic regimen needs to be identified and provided while managing systemic limitations that could secondarily limit the healing response. Unfortunately, most current solutions seem to aim at designing therapeutic regimen with little or no consideration of the specific details of the wound environment and systemic limitations. One factor that is centrally important in making the wound environment receptive is correction of wound hypoxia. Recent work have identified that oxygen is not only required to disinfect wounds and fuel healing but that oxygen-dependent redox-sensitive signaling processes represent an integral component of the healing cascade. Over a decade ago, it was proposed that in biological systems oxidants are not necessarily always the triggers for oxidative damage and that oxidants such as H(2)O(2) could actually serve as signaling messengers and drive several aspects of cellular signaling. Today, that concept is much more developed and mature. Evidence supporting the role of oxidants such as H(2)O(2) as signaling messenger is compelling. A complete understanding of the continuum between the classical and emergent roles of oxygen requires a thorough consideration of current concepts in redox biology. The objective of this review is to describe our current understanding of how redox-sensitive processes may drive dermal tissue repair.     

Collagen reorganization in leech wound healing

BACKGROUND INFORMATION: Leeches respond to surgical lesions with the same sequence of events as that described for wound healing in vertebrates, where collagen is important for the development of tensions in healing wounds, functioning as an extracellular scaffold for accurate regeneration of the structures disrupted by surgical or traumatic actions. RESULTS: In surgically lesioned leeches, newly synthesized collagen is arranged in hierarchical structures. Fibrils can be packed and shaped to form cords or tubular structures, thus acting as an extracellular scaffold that directs and organizes the outgrowth of new vessels and the migration of immune cells towards lesioned tissues. In these animals, the general architecture of collagen fibrils, generated during tissue regeneration, shows similarities to both the structural pattern of collagen bundles and assembly processes observed in several vertebrate systems (fish scales, amphibian skin and human cornea). CONCLUSIONS: The production of extracellular matrix during wound healing in leeches is a surprising example of conservation of an extremely close relationship between the structure and function of molecular structures. It could be hypothesized that collagen structures, characterized not only by a striking structural complexity, but also by multifunctional purposes, are anatomical systems highly conserved throughout evolution.