Role of cytokines and cytokine therapy in wound healing and fibrotic diseases

Cytokines are critical to a myriad of fundamental homeostatic and pathophysiological processes such as fever, wound healing, inflammation, tissue repair and fibrosis. They play important roles in regulating cell function such as proliferation, migration, and matrix synthesis. It is the balance or the net effect of the complex interplay between these mediators, which appears to play a major role in regulating the initiation, progression and resolution of wounds. Wound healing involves a complex process including induction of acute inflammation by the initial injury, followed by parenchymal and mesenchymal cell proliferation, migration, and activation with production and deposition of extracellular matrix. Failure to resolve or abnormal wound healing results in fibrosis. The latter process involves similar cellular interactions via complex cytokine networks, which result in extensive remodeling with heightened extracellular matrix production and their abnormal deposition in the tissue. Various cytokines, both promoting and inhibiting fibrogenesis, have been implicated in the pathogenesis of fibrosis and wound healing. Recent progress in understanding the mechanisms underlying the pathogenesis of fibrosis leads us to expect that inhibitors of pro-fibrogenic cytokines and growth factors may be useful as novel therapeutic agents in controlling undesirable fibrosis. In this review, the role of cytokines in wound healing and fibrosis will be summarized and highlighted with more detailed discussion reserved for the possible points of therapeutic attack in pulmonary fibrosis. In this review, the major cytokines that are in current clinical use will be also discussed. In addition, advances in the application of novel cytokines and anti-cytokines for accelerating wound healing and attenuating fibrosis both at the experimental and the clinical trial levels will be discussed.     

Wound healing: a new approach to the topical wound care

Cutaneous wound healing is a complex and well-coordinated interaction between inflammatory cells and mediators, establishing significant overlap between the phases of wound healing. Wound healing is divided into three major phases: inflammatory phase, proliferative phase, and remodeling phase. Unlike the acute wound, the nonhealing wound is arrested in one of the phases of healing, typically the inflammatory phase. A systematic approach to the management of the chronic nonhealing wound emphasizes three important elements of wound bed preparation in chronic wounds: debridement, moisture, and countering bacterial colonization and infection. In this article, wound-healing process and new approaches to the topical wound care have been reviewed.     

Wound healing: a new approach to the topical wound care

Cutaneous wound healing is a complex and well-coordinated interaction between inflammatory cells and mediators, establishing significant overlap between the phases of wound healing. Wound healing is divided into three major phases: inflammatory phase, proliferative phase, and remodeling phase. Unlike the acute wound, the nonhealing wound is arrested in one of the phases of healing, typically the inflammatory phase. A systematic approach to the management of the chronic nonhealing wound emphasizes three important elements of wound bed preparation in chronic wounds: debridement, moisture, and countering bacterial colonization and infection. In this article, wound-healing process and new approaches to the topical wound care have been reviewed.     

The role of antioxidants in models of inflammation: Emphasis on l-arginine and arachidonic acid metabolism

Inflammatory processes are made up of a multitude of complex cascades. Under physiological conditions these processes aid in tissue repair. However, under pathophysiological environments, such as wound healing and hypoxia-ischaemia (HI), inflammatory mediators become imbalanced, resulting in tissue destruction. This review addresses the changes in reactive oxygen species (ROS), l-arginine and arachidonic acid metabolism in wound healing and HI and subsequent treatments with promising anti-oxidants. Even though these models may appear divergent, anti-oxidant treatments are nevertheless still having favourable effects. On the basis of recent findings, it is apparent that protection with anti-oxidants is not solely attributed to scavenging of ROS. In addition, the actions of anti-oxidants must be considered in light of the inflammatory process being assessed. To this end, there does not appear to be any universally applicable single mechanism to explain the actions of anti-oxidants.     

T淋巴细胞与创伤愈合

机体在受到创伤后全身和局部的免疫状态会发生复杂的变化。免疫系统除了在机体防御及炎症反应中起作用，还通过免疫细胞产生多种细胞因子对创伤愈合过程进行调节，并伴随创伤修复的整个过程。T淋巴细胞是参与细胞免疫反应的主要细胞之一，它通过识别抗原并产生各种细胞因子来参与创伤愈合的调控。完整的细胞免疫反应对良好的组织修复是必需的，而各种导致淋巴细胞功能低下的因素会延缓伤口愈合。该文就创伤后T淋巴细胞的变化及其在创伤愈合中的作用等方面作一介绍。     

Targeting matrix metalloproteases to improve cutaneous wound healing

Wound repair is a physiological event in which tissue injury initiates a repair process leading to restoration of structure and function of the tissue. Cutaneous wound repair can be divided into a series of overlapping phases including formation of fibrin clot, inflammatory response, granulation tissue formation incorporating re-epithelialisation and angiogenesis and finally, matrix formation and remodelling. Matrix metalloproteases (MMPs) are a family of neutral proteases that play a vital role throughout the entire wound healing process. They regulate inflammation, degrade the extracellular matrix (ECM) to facilitate the migration of cells and remodel the new ECM. However, excessive MMP activity contributes to the development of chronic wounds. Selective control of MMP activity may prove to be a valuable therapeutic approach to promote healing of chronic ulcers. Recent evidence indicates that the anticoagulant, activated protein C may be useful in the treatment of non-healing wounds by preventing excessive protease activity through inhibition of inflammation and selectively increasing MMP-2 activity to enhance angiogenesis and re-epithelialisation.     

Targeting matrix metalloproteases to improve cutaneous wound healing

Wound repair is a physiological event in which tissue injury initiates a repair process leading to restoration of structure and function of the tissue. Cutaneous wound repair can be divided into a series of overlapping phases including formation of fibrin clot, inflammatory response, granulation tissue formation incorporating re-epithelialisation and angiogenesis and finally, matrix formation and remodelling. Matrix metalloproteases (MMPs) are a family of neutral proteases that play a vital role throughout the entire wound healing process. They regulate inflammation, degrade the extracellular matrix (ECM) to facilitate the migration of cells and remodel the new ECM. However, excessive MMP activity contributes to the development of chronic wounds. Selective control of MMP activity may prove to be a valuable therapeutic approach to promote healing of chronic ulcers. Recent evidence indicates that the anticoagulant, activated protein C may be useful in the treatment of non-healing wounds by preventing excessive protease activity through inhibition of inflammation and selectively increasing MMP-2 activity to enhance angiogenesis and re-epithelialisation.     

Growth factor regulation and manipulation in wound repair: to scar or not to scar,that is the question

The process of tissue repair following injury is in the large part mediated by secreted growth factors which, in an autocrine or paracrine fashion, stimulate immune and mesenchymal cells at the site of injury. The complex process of replacing damaged tissue with newly formed tissue involves components of the blood, coagulation, immune and mesenchymal systems as well as cytokines, chemokines, metalloproteinases and growth factors. This review will focus on growth factors as the controllers of this process and includes members of the transforming growth factor (TGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), connective tissue derived growth factor (CTGF) and insulin-like growth factor-I (IGF-I) families of growth factors. These growth factors stimulate re-epithelialisation, angiogenesis, extracellular matrix (ECM) formation and cell proliferation each of which plays a role in tissue replacement and restoration of tissue function following injury. Normal wound healing frequently involves the formation of scar tissue, including increased mesenchymal cell proliferation and excessive production of ECM proteins. While scar tissue rapidly and effectively closes wounds, it leaves visually apparent tissue structure changes and may reduce the function of the tissue leading to compromised organ function. Growth factors, the conductors of these processes, are targets for therapeutic manipulation of wound healing and scar formation. Recent patents involving growth factors may be implicated in the treatment of wound healing following tissue injury. Enhanced growth factor activity may be beneficial to increase the rate of wound healing in chronic non-healing wounds, whereas reduction of growth factor presence or activity may reduce scar formation in the skin and internal organs, which may be particularly relevant where scar formation is associated with pathologic loss of life sustaining organ function.     

Inflammatory response in molluscs: cross-taxa and evolutionary considerations

Inflammation represents the rapid and efficient elimination of damaged tissue and microbes and eventually the restoration of tissue functionality. Inflammatory response is one of the vital reactions to body injury, acting alongside the restoration of homeostasis, wound repair and immune response. In mammals, wound healing is a process that seeks to restore tissue integrity and function, and is characterized by a series of biological processes including inflammatory response. Here, we review pioneering experiments and recent observations in invertebrate models suggesting that in highly divergent and evolutionary distant taxa, such as molluscs, insects and vertebrates, the inflammatory response could be driven by a pool of molecules sharing common evolutionary origin.     

Current evidence on immunological and regenerative effects of menstrual blood stem cells seeded on scaffold consisting of amniotic membrane and silk fibroin in chronic wound

Wound healing process is a complex of overlapping and coordinated events progresses beyond the inflammatory phase toward wound resolution, whereas chronic wounds fail to terminate inflammatory phase and could not develop toward regenerative state. The immunopathology of chronic wounds has been attributed to the prolonged inflammation and dysregulation of microenvironments responsible for imbalance between pro-inflammatory and anti-inflammatory states, as well as cellular and tissue senescence.We here discuss that menstrual blood-derived mesenchymal stem cells (MenSCs) with their authentic functions especially immunosuppressive, angiogenic and migratory properties in combination with a bilayer amniotic membrane/nano-fibrous fibroin scaffold could bring about effective regenerative effects in healing of chronic wound. To debate, following evidences have been cumulated : 1) Persistent pro-inflammatory state in chronic wound bed could inhibit wound resolution; 2) MenSCs exhibit noticeable regenerative, immunosuppressive effects and immunomodulatory activity, 3) The migratory characteristics of MenSCs may not be sufficient for their homing to chronic wounds site, and 4) Bilayer scaffold composed of amniotic membrane and silk fibroin induces MenSCs differentiation into keratinocyte-like cells and stimulates skin regeneration.     

Invalid freeze-dried platelet gel promotes wound healing

Wound healing is the curative process of tissue injury, composed of three phases: the inflammatory phase, proliferative phase, followed by the maturation cum remodeling phase. Various treatment options were previously depicted for wound healing, however a treatment that accelerates these phases would be highly valuable. Platelet aggregation at the bleeding vessels and release of various growth factors are the most promising factors that stimulates the wound healing progress. In the present study, we hypothesized that the freeze-dried platelet which were normally discarded from the blood banks due to invalidity, might be promising to accelerate the phases of wound healing. The invalid freeze-dried platelets were prepared to a gel form called invalid freeze-dried platelet gel (IF-PG), which was tested for its efficacy in a cutaneous punch wound model in rats. Mupirocin antibiotic gel was used as a bio-equivalent formulation. The wound healing phases and changes in the wound sites were determined by assessing the wound sizes, histopathological analysis, immunohistochemical staining. The re-epithelialization at the wound sites at different time intervals till the wound closure was also determined. Our results suggest the beneficial effects of IF-PG; in reducing the wound area and accelerating wound closure in the cutaneous punch wound in rats. Histopathology and immunostaining results support the improvements in the wound when treated with IF-PG, which were similar to that of mupirocin antibiotic gel. Our preliminary findings also warrant the competency of IF-PG in modulating the different phases of wound healing process. In conclusion, IF-PG might be a resourceful alternative for the wound care management, however further studies are required to validate its impact on various growth factors before proceeding to clinical studies.     

Recent patents on topical application of honey in wound and burn management

Topical application of honey to burn and wounds has been found to be effective in controlling infection and producing a clean granulating bed. It is suggested that the wound healing effect of honey may in part be related to the release of inflammatory cytokines from surrounding tissue cells, mainly monocytes and macrophages. It has been reported that honey hastens wound healing by accelerating wound contractions. Microscopic evaluation demonstrated that there was a significant acceleration of dermal repair in wound treated with honey. Macroscopic and microscopic observations under in vivo assessment suggested that the topical application of honey might have favourable influences on the various phases of burn and wound healing hence accelerating the healing process. The regulatory effects of honey are related to components other than the sugars. However, the mechanisms by which honey affects the release of anti inflammatory agents and growth factors from monocytic cells are as yet unclear. Whether honey affects other cell types, particularly endothelial cells and fibroblasts, involved in wound healing also needs to be clarified. The present article is a short review of recent patents on the healing effect of honey in wound and burn management.     

外泌体源性微 RNA与肛瘘术后创面愈合的研究进展

肛瘘作为常见的肛肠疾病，目前以手术治疗为主，但由于术后创面易被粪便污染，大多不做缝合，因此抑制创面炎症的发生以及促进创面的修复和愈合对于病人预后显得极为重要。近期有研究表明，外泌体在免疫调节、抑制炎症反应和修复受损组织等方面具有良好的应用前景，它是一种携带 DNA、RNA和蛋白质等多种生物活性物质的脂质双分子层囊泡，并通过自分泌或旁分泌的方式参与细胞之间的通信及各种生物学过程。其中，微 RNA(miRNA)作为一种非编码 RNA分子，以外泌体为载体，同样在各种生理病理过程中起到重要作用。因此，该研究旨在总结外泌体源性 miRNA对于肛瘘术后创面炎症和愈合的研究进展，以分析其潜在应用价值。     

Platelet interaction with progenitor cells: vascular regeneration or inquiry?

Increasing evidence supports the role of stem and progenitor cells in vascular regeneration or injury. Following tissue ischemia, progenitor cells are mobilized from their bone marrow or peripheral niches into circulation, adhere at sites of vascular lesion and differentiate into a variety of mature cell types according to their origin and the local environment. Impairment in this pathophysiological process due to either low numbers of circulating progenitor cells or dysfunctional progenitor cells leads to inadequate vascular repair and upon co-existence with different cardiovascular risk factors to vascular injury and atherosclerosis. Vascular repair is a complex process which includes mobilization, chemotaxis, adhesion, proliferation and differentiation of progenitor cells. The common cardiovascular risk factors can impair this process resulting into inhibition of vascular healing and enhancement of inflammatory pathways which ultimately leads to atherosclerosis. Although homing of progenitor cells into bone marrow has been extensively studied, domiciliation of precursor cells into peripheral tissues and differentiation into mature cells are poorly understood so far. Recently, the role of platelets in domiciliation and subsequent differentiation of progenitor cells has been highlighted. Adherent platelets recruit circulating progenitor cells in vitro and in vivo and induce differentiation of the latter into endothelial cells or macrophages and foam cells. Although further studies are needed to describe the mechanisms that lie underneath these observations, it seems that platelet interaction with progenitor cells is an essential step in both vascular regeneration and injury.     

In vitro evaluation of chloroaluminum phthalocyanine nanoemulsion and low-level laser therapy on human skin dermal equivalents and bone marrow mesenchymal stem cells

Nanotechnology and tissue engineering are promising scientific fields in the development of advanced materials useful to human health. This article describes the preparation of a nanocarrier for the controlled release of a photosensitizer compound associated with low-level light therapy for skin wound healing treatment and applicable to other skin diseases. A biological model was used as an in vitro skin equivalent based on a three-dimensional culture of fibroblasts and mesenchymal stem cells and denominated by dermal equivalent (DE). Results show that it is possible to use the photomodulation process to control the wound healing in a scratching process and to induce the biomolecules release, both of which are related with the inflammatory wound healing process. In the studies, the MMP-2 and MMP-9 expression from zymography analyses were evaluated. All results showed a dependence on enzymatic activity relating to lowlevel laser applications which indicates a potential application in wound healing processes based on phototherapy and nanotechnology.     

Adenosine receptor agonists for promotion of dermal wound healing

Wound healing is a dynamic and complex process that involves a well-coordinated, highly regulated series of events including inflammation, tissue formation, revascularization and tissue remodeling. However, this orderly sequence is impaired in certain pathophysiological conditions such as diabetes mellitus, venous insufficiency, chronic glucocorticoid use, aging and malnutrition. Together with proper wound care, promotion of the healing process is the primary objective in the management of chronic poorly healing wounds. Recent studies have demonstrated that A_2A adenosine receptor agonists promote wound healing in normal and diabetic animals and one such agonist, Sonedenoson, is currently being evaluated as a prospective new therapy of diabetic foot ulcers. We will review the mechanisms by which adenosine receptor activation affects the function of the cells and tissues that participate in wound healing, emphasizing the potential beneficial impact of adenosine receptor agonists in diabetic impaired healing.     

Possible anti-inflammatory role of COX-2-derived prostaglandins: implications for inflammation research

Inflammation is the response of any tissue to injury or trauma. The inflammatory response forms the basis of several pathological and pathophysiological processes, including wound healing, rheumatoid arthritis and neurodegenerative disorders, including Alzheimer's disease and stroke. The response is mediated by various signaling molecules and enzymatic pathways, among which the cyclooxygenase (COX) pathway is one of the most predominant. COX catalyzes the formation of prostaglandins and thromboxanes from arachidonic acid (AA). In 1971, Sir John Vane demonstrated for the first time that the mechanism of action of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is via inhibition of COX. Since the discovery of at least two isoforms of COX, inhibition of COX-2 has generally been considered the basis for the anti-inflammatory effects of NSAIDs. However, more recent studies of COX-2 have controversially postulated that the selective inhibition of COX-2 may not be beneficial, but rather can be detrimental. This is based on the observations that, during inflammation, not all AA-derived mediators are exclusively pro-inflammatory. This review will attempt to discuss the confusing and contradictory data relating to selective COX-2 inhibition and inflammation, particularly focusing on anti-inflammatory AA-derived mediators. We will also try to advance the perspective that inflammation is not just a single process, but is rather a dynamic and continuously changing event, not just in terms of time, mediators and cells, but also in the initiating stimuli, whether it be in the periphery or the central nervous system.     

Peroxisome proliferator-activated receptor-beta as a target for wound healing drugs

Healing of cutaneous wounds, which is crucial for survival after an injury, proceeds via a well-tuned pattern of events including inflammation, re-epithelialisation, and matrix and tissue remodelling. These events are regulated spatio-temporally by a variety of growth factors and cytokines. The inflammation that immediately follows injury increases the expression of peroxisome proliferator-activated receptor (PPAR)-beta in the wound edge keratinocytes and triggers the production of endogenous PPARbeta ligands that activate the newly produced receptor. This elevated PPARbeta activity results in increased resistance of the keratinocytes to the apoptotic signals released during wounding, allowing faster re-epithelialisation. The authors speculate that, in parallel, ligand activation of PPARbeta in infiltrated macrophages attenuates the inflammatory response, which also promotes repair. Thus, current understanding of the roles of PPARbeta in different cell types implicated in tissue repair has revealed an intriguing intercellular cross-talk that coordinates, spatially and temporally, inflammation, keratinocyte survival, proliferation and migration, which are all essential for efficient wound repair. These novel insights into the orchestrating roles of PPARbeta during wound healing may be helpful in the development of drugs for acute and chronic wound disorders.     

Mast cells in tissue healing: from skin to the gastrointestinal tract

Mast cells are largely found at interfaces between the environment and the internal milieu. Early knowledge of the mast cell suggested a role predominantly associated with allergy and pathologic response to antigens, but more recent research has shown a myriad of functions is likely. Wound healing is a complex process of lysis and reconstitution controlled by a series of cell signalling proteins. Mast cells have been shown to play a significant role in the early inflammatory stage of wound healing and also influence proliferation and tissue remodelling in skin. Emerging work implicates the mast cell as a modulator of intestinal healing particularly following surgical anastomosis. The study of mast cells and wound healing involves the use of cell studies and animal models through the use of mast cell inhibitors, promoters and mast cell deficient rodent strains. This review addresses wound healing in skin and the gastrointestinal tract and specifically identifies data pertaining to the role of the mast cell in the process of cell breakdown, repair and regeneration.