Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

Origin and Physiological Roles of Inflammation

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.

Oxidative stress and diabetic complications

Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling For a wound to heal successfully, all four phases must occur in the proper sequence and time frame Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds

Factors Affecting Wound Healing

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion

Background: Macromastia has been considered a contraindication to breast conservation therapy because of difficulties with radiation therapy. This study evaluates the feasibility of bilateral reduction mammoplasty as a component of breast conservation therapy for breast cancer patients with pendulous breasts. Methods: Of 153 patients undergoing reduction mammoplasty at the University of Texas M. D. Anderson Cancer Center, 28 were identified as breast cancer patients with macromastia receiving breast conservation therapy. Median follow-up was 23.8 months. Results: Median patient age was 55 years. Nearly all patients were described as obese. Median weight of the reduction mammoplasty specimen on the cancerous side was 766 g. One patient (4%) required completion mastectomy for inadequate margin control. Major postoperative complications occurred in 2 patients (7%). There were no major postradiation complications. Patient survey revealed a satisfaction rate of 86%. Conclusion: Bilateral reduction mammoplasty is a reasonable and safe option for breast cancer patients with macromastia who desire breast conservation therapy.

Reduction mammoplasty improves breast conservation therapy in patients with macromastia.

More than 200 million incisions are made in the world each year, all of which result in scarring, which is the body’s natural response to cutaneous tissue injury.1,2 Scarring creates both functional and aesthetic impairments and is associated with considerable psychosocial stress. Although there is currently no level I evidence for scar mitigation therapy, several procedures are widely used to reduce the impact of postsurgical scars. Revision surgery is the traditional treatment for improving scar appearance, generally focusing on either making the scar less noticeable or reframing the scar geometry so that it appears more like a natural anatomical crease.3,4 In the United States alone, more than 170,000 scar revision procedures were performed in 2011.5 Laser treatments have become increasingly popular in the past two decades, including carbon dioxide and pulsed dye lasers, and dermabrasion therapy is frequently used to smooth scars with irregular topology.6,7 Silicone gels, sheets, and tapes have also been used to minimize scarring postoperatively.8–10 Similarly, topical creams containing ingredients such as retinoic acid and onion extract have been used to reduce scar intensity, as have intralesional therapies containing corticosteroids or biomolecules.11,12 However, even the most scientifically grounded of these approaches, the human transforming growth factor-β3 drug Juvista (Renovo, Manchester, United Kingdom), failed to achieve efficacy in a phase III clinical trial.13

The impact of mechanical forces on fibrosis and scar formation has been known for over 100 years. Surgeons routinely strive to make incisions parallel to the Langer lines, corresponding to the orientation of native collagen fibers in the dermis, to minimize tension across the wound. Despite this intuitive knowledge of the relationship between mechanical force and scar formation, until recently, few studies had thoroughly explored the physiologic mechanisms underlying this interaction, and therapeutics aimed at reducing scarring through mechanomodulation have not been widely available.

A recent report involving both pig and human incisions treated with a tension-shielding device postoperatively showed a highly significant reduction in scarring.14 Furthermore, the biology underlying mechanomodulation to reduce fibrosis in scarring of cutaneous wounds has been rigorously studied in a transgenic mouse model.15 These basic science and clinical studies strongly support a strategy for shielding healing wounds from mechanical forces to reduce scarring.

In this article, we report clinical data using the embrace (Neodyne Biosciences, Inc., Menlo Park, Calif.) device following scar revision and potentially address the large unmet clinical need for significantly improving scar appearance following revision surgery. The embrace device creates a tension shield around the healing wound, which results in a reduced-stress environment conducive to wound healing with minimal fibrosis and scarring.14 We demonstrate the efficacy of this device through a randomized controlled trial of scar revision in 12 patients evaluated by four independent surgeons using a visual analogue scale system.

The embrace device significantly decreases scarring following scar revision surgery in a randomized controlled trial.

The role of focal adhesion complexes in fibroblast mechanotransduction during scar formation

The hedgehog family of morphogens (sonic [Shh], Indian, and desert hedgehog) are central regulators of embryologic growth and tissue patterning. Although recent work implicates Shh in postnatal tissue repair and development, conclusive evidence is lacking. Here, we demonstrated the importance of Shh in wound repair, by examining the effects of cyclopamine, a specific inhibitor of the Shh signaling cascade, on tissue repair. Using a murine-splinted excisional wound model, which attenuates wound contraction in this loose-skinned rodent, we established that, by all measures (wound closure, epithelialization, granulation formation, vascularity, and proliferation), wound healing was profoundly impaired when Shh signaling was disrupted. Because embryonic disruption of Shh is associated with distinct phenotypic defects, our findings invite investigation of the potential role of Shh signaling under postnatal conditions associated with disregulated wound healing.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1524-475X.2008.00430.x

Hedgehog signaling is essential for normal wound healing

Hemangiomas are the most common tumor of infancy, and although the natural history of these lesions is well described, their etiology remains unknown. One current theory attributes the development of hemangiomas to placentally-derived cells; however, conclusive evidence to support a placental origin is lacking. While placental tissue and hemangiomas do share molecular similarities, it is possible that these parallels are the result of analogous responses of endothelial cells and vascular progenitors to similar environmental cues. Specifically, both tissue types consist of actively proliferating cells that exist within a low oxygen, high estrogen environment. The hypoxic environment leads to an upregulation of hypoxia inducible factor-1α (HIF-1α) responsive chemokines such as stromal cell derived factor-1α (SDF-1α) and vascular endothelial growth factor (VEGF), both of which are known to promote the recruitment and proliferation of endothelial progenitor cells. Increased hormone levels in the postpartum pe...

Geoffrey C. Gurtner

Papers

Reduction mammoplasty improves breast conservation therapy in patients with macromastia.

The embrace device significantly decreases scarring following scar revision surgery in a randomized controlled trial.

The role of focal adhesion complexes in fibroblast mechanotransduction during scar formation

Hedgehog signaling is essential for normal wound healing

Hypoxia, hormones, and endothelial progenitor cells in hemangioma.