Skewing cPLAα activity toward oxoeicosanoid production promotes neutrophil N2 polarization, wound healing, and the response to sepsis.

Uncontrolled inflammation is linked to poor outcomes in sepsis and wound healing, both of which proceed through distinct inflammatory and resolution phases. Eicosanoids are a class of bioactive lipids that recruit neutrophils and other innate immune cells. The interaction of ceramide 1-phosphate (C1P) with the eicosanoid biosynthetic enzyme cytosolic phospholipase A (cPLA) reduces the production of a subtype of eicosanoids called oxoeicosanoids.

Ceramide kinase regulates acute wound healing by suppressing 5-oxo-ETE biosynthesis and signaling via its receptor OXER1.

The sphingolipid, ceramide-1-phosphate (C1P), has been shown to promote the inflammatory phase and inhibit the proliferation and remodeling stages of wound repair via direct interaction with group IVA cytosolic phospholipase A, a regulator of eicosanoid biosynthesis that fine-tunes the behaviors of various cell types during wound healing. However, the anabolic enzyme responsible for the production of C1P that suppresses wound healing as well as bioactive eicosanoids and target receptors that drive enhanced wound remodeling have not been characterized. Herein, we determined that decreasing C1P activity via inhibitors or genetic ablation of the anabolic enzyme ceramide kinase (CERK) significantly enhanced wound healing phenotypes.

What Makes Wounds Chronic.

Chronic wounds present a unique therapeutic challenge to heal. Chronic wounds are colonized with bacteria and the presence of a biofilm that further inhibits the normal wound healing processes, and are locked into a very damaging proinflammatory response. The treatment of chronic wounds requires a coordinated approach, including debridement of devitalized tissue, minimizing bacteria and biofilm, control of inflammation, and the use of specialized dressings to address the specific aspects of the particular nonhealing ulcer.

The interaction of ceramide 1-phosphate with group IVA cytosolic phospholipase A coordinates acute wound healing and repair.

The sphingolipid ceramide 1-phosphate (C1P) directly binds to and activates group IVA cytosolic phospholipase A (cPLAα) 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 cPLAα and in knock-in (KI) mice in which endogenous cPLAα 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.

Network proteomics of human dermal wound healing.

Objective: The healing of wounds is critical in protecting the human body against environmental factors. The mechanisms involving protein expression during this complex physiological process have not been fully elucidated.

Approach: Here, we use reverse-phase protein microarrays (RPPA) involving 94 phosphoproteins to study tissue samples from tubes implanted in healing dermal wounds in seven human subjects tracked over two weeks.

Human as the Ultimate Wound Healing Model: Strategies for Studies Investigating the Dermal Lipidome.

Purpose Of Review: Educate the reader of the multiple roles undertaken by the human epidermal lipidome and the experimental techniques of measuring them.

Recent Findings: Damage to skin elicits a wound healing process that is capped by the recreation of the lipid barrier. In addition to barrier function, lipids also undertake an active signaling role during wound healing.

Modeling the effects of systemic mediators on the inflammatory phase of wound healing.

The normal wound healing response is characterized by a progression from clot formation, to an inflammatory phase, to a repair phase, and finally, to remodeling. In many chronic wounds there is an extended inflammatory phase that stops this progression. In order to understand the inflammatory phase in more detail, we developed an ordinary differential equation model that accounts for two systemic mediators that are known to modulate this phase, estrogen (a protective hormone during wound healing) and cortisol (a hormone elevated after trauma that slows healing).

Ceramide kinase is required for a normal eicosanoid response and the subsequent orderly migration of fibroblasts.

In these studies, the role of ceramide-1-phosphate (C1P) in the wound-healing process was investigated. Specifically, fibroblasts isolated from mice with the known anabolic enzyme for C1P, ceramide kinase (CERK), ablated (CERK(-/-) mice) and their wild-type littermates (CERK(+/+)) were subjected to in vitro wound-healing assays. Simulation of mechanical trauma of a wound by scratching a monolayer of fibroblasts from CERK(+/+) mice demonstrated steadily increasing levels of arachidonic acid in a time-dependent manner in stark contrast to CERK(-/-) fibroblasts.

Structural Stereochemistry of Androstene Hormones Determines Interactions with Human Androgen, Estrogen, and Glucocorticoid Receptors.

DHEA, 17-AED, 17-AED, and 17-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17-AED, 17-AED, and 17-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators.

A Network Approach to Wound Healing.

Objective: The wound healing process is well-understood on the cellular and tissue level; however, its complex molecular mechanisms are not yet uncovered in their entirety. Viewing wounds as perturbed molecular networks provides the tools for analyzing and optimizing the healing process. It helps to answer specific questions that lead to better understanding of the complexity of the process.

Preclinical Models of Wound Healing: Is Man the Model? Proceedings of the Wound Healing Society Symposium.

Significance: A review of therapeutic effects in preclinical and clinical studies suggests that concordance between large animal (pig=78%), small laboratory animal (53%) and (57%) results with those observed in humans is only partial. Pig models of wound healing provide major advantages over other animal models. Since the vast majority of wound-healing research is done in rodents and , the low concordance rate is a significant impediment to research that will have any clinical impact.

An entropy-based automated cell nuclei segmentation and quantification: application in analysis of wound healing process.

The segmentation and quantification of cell nuclei are two very significant tasks in the analysis of histological images. Accurate results of cell nuclei segmentation are often adapted to a variety of applications such as the detection of cancerous cell nuclei and the observation of overlapping cellular events occurring during wound healing process in the human body. In this paper, an automated entropy-based thresholding system for segmentation and quantification of cell nuclei from histologically stained images has been presented.

A differential equation model of collagen accumulation in a healing wound.

Wound healing is a complex biological process which involves many cell types and biochemical signals and which progresses through multiple, overlapping phases. In this manuscript, we develop a model of collagen accumulation as a marker of wound healing. The mathematical model is a system of ordinary differential equations which tracks fibroblasts, collagen, inflammation and pathogens.

Systemic central venous oxygen saturation is associated with clot strength during traumatic hemorrhagic shock: A preclinical observational model.

Background: Clot strength by Thrombelastography (TEG) is associated with mortality during trauma and has been linked to severity of tissue hypoperfusion. However, the optimal method for monitoring this important relationship remains undefined. We hypothesize that oxygen transport measurements will be associated with clot strength during traumatic shock, and test this hypothesis using a swine model of controlled traumatic shock.

Wound healing primer.

Surgeons often care for patients with conditions of abnormal wound healing, which include conditions of excessive wound healing, such as fibrosis, adhesions, and contractures, as well as conditions of inadequate wound healing, such as chronic nonhealing ulcers, recurrent hernias, and wound dehiscences. Despite many recent advances in the field, which have highlighted the importance of adjunct therapies in maximizing the healing potential, conditions of abnormal wound healing continue to cause significant cost, morbidity, and mortality. To understand how conditions of abnormal wound healing can be corrected, it is important to first understand the basic principles of wound healing.

An in silico approach to the analysis of acute wound healing.

The complex interactions that characterize acute wound healing have stymied the development of effective therapeutic modalities. The use of computational models holds the promise to improve our basic approach to understanding the process. By modifying an existing ordinary differential equation model of systemic inflammation to simulate local wound healing, we expect to improve the understanding of the underlying complexities of wound healing and thus allow for the development of novel, targeted therapeutic strategies.

Androstenediol reverses steroid-inhibited wound healing.

It is well recognized that stress of any nature will cause a delay in the wound healing response. This delayed healing response appears closely associated with immune regulators. In this study, CD-1 mice were injected with a long acting form of methyl prednisolone to cause a steroid-induced immune suppression.

Primary cultured fibroblasts derived from patients with chronic wounds: a methodology to produce human cell lines and test putative growth factor therapy such as GMCSF.

Background: Multiple physiologic impairments are responsible for chronic wounds. A cell line grown which retains its phenotype from patient wounds would provide means of testing new therapies. Clinical information on patients from whom cells were grown can provide insights into mechanisms of specific disease such as diabetes or biological processes such as aging.

Biologic therapeutics and molecular profiling to optimize wound healing.

Non-healing wounds represent a significant cause of morbidity and mortality for a large portion of the adult population. Wounds that fail to heal are entrapped in a self-sustaining cycle of chronic inflammation leading to the destruction of the extracellular matrix. Among cancer patients, malnutrition, radiation, physical dehabilitation, chemotherapy, and the malignancy itself increase the likelihood of chronic wound formation, and these co-morbidity factors inhibit the normal wound healing process.

Multidisciplinary panel discussion of a gynecologic oncology patient: preventing wound complications.

At the 39th meeting of the Society of Gynecologic Oncologists, a multidisciplinary panel presented and discussed the current management strategies for the treatment of complex wounds. After the presentations, the panel discussed the management options for a morbidly obese endometrial cancer patient with a focus toward the complex wound that may delay discharge, healing, or the start of adjuvant treatment. This article highlights the clinical considerations discussed for these types of patients.

Androstenetriol immunomodulation improves survival in a severe trauma hemorrhage shock model.

Background: Traumatic shock activates the hypothalamic-pituitary-adrenal axis (HPA) to mediate a cascade of defensive mechanisms that often include overwhelming inflammatory response and immunosuppression, which may lead to multiple organ failure. Androstenetriol (5 androstene, 3beta, 7beta, 17beta triol-AET) is a metabolite of dehydroepiandrosterone that markedly up regulates host immune response, prevents immune suppression, modulates inflammation and improves survival after lethal infections by pathogens and lethal radiation.

Hypothesis: AET-induced immune modulation will improve survival in a conscious rodent model of traumatic shock.

Regulation of fibroblast functions by lysophospholipid mediators: potential roles in wound healing.

The bioactive lysophospholipids, primarily lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), are recent additions to the list of potent mediators of tissue repair and wound healing. In this review, we highlight the diverse actions of LPA and S1P on many types of cells involved in the wound healing process, with special emphasis on their regulation of fibroblasts. The effects of LPA and S1P are principally mediated via specific cell surface receptors.

Comparison of a new hemostatic agent to current combat hemostatic agents in a Swine model of lethal extremity arterial hemorrhage.

Background: Gaining hemostatic control of lethal vascular injuries sustained in combat using topical agents remains a challenge. Recent animal testing using a lethal arterial injury model has demonstrated that QuikClot zeolite granules (QCG) and the HemCon chitosan bandage (HC) are not capable of providing hemostasis and improving survival over the Army gauze field bandage (AFB). We have developed a new hemostatic agent consisting of a granular combination of a smectite mineral and a polymer (WoundStat) capable of producing hemostasis in the face of high-pressure arterial bleeding.