Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 10, Issue 4, 2010

Wound healing process may lead to undesirable outcome, tissue fibrosis or scarring, and affect the organ function in various organs. Body surface, i. e., skin, mucosa including ocular surface, directly receive external stimuli, and injured.Excess scarring in such tissues is to be prevented to maintain their function or an outward appearance of a patient. Surface epithelium and underlying mesenchymal cells, as well as inflammatory cells, are involved in the wound healing in these tissues. Wellorganized cell behaviors are essential to the restoration of normal function of the skin or ocular surface. In this mini-hot topic issue, we have three articles focusing on wound healing and fibrosis in skin and ocular surface, as well as the role of epithelial integrin on wound healing-related cytokine signaling. Understanding the mechanism of wound healing of such organs is essential to develop new prevention strategies of undesirable fibrosis or scarring.

Fibrosis could occur in virtually any organ or tissue. The fibrotic lesion indolently disrupts the structure of the healthy organ, thereby hampering its proper function, consequence of which is devastating. Among the myriad factors that modulate fibrogenesis, transforming growth factor β (TGF-β) is one of the most studied and its central role for fibrotic disorders has been strongly suggested. Due to the pleiotropic nature of this cytokine, TGF-β modulates multiple cellular responses throughout fibrogenesis. The complexity is supported by the TGF-β receptor-specific phosphorylation of both the canonical, Smad-, and non-canonical, “non-Smad,” pathways. The latter modulates Smad activity either independent of Smad or by phosphorylating the Smad linker region, distinct from those receptor-regulated. Despite the commodity of this mediator, the mechanism by which TGF-β signaling causes specific pathogenesis and disease varies depending on the nature of the organ and the cells that compose that organ. Cells express a specific series of integrins that act as cellular sensors for the extracellular environment, determining subsequent cellular signals in a cell-type specific manner. Integrins may change their expression pattern under pathological conditions and contribute to the regulation of fibrogenesis via modulating ambient TGF-β activity. This regulation includes release of active TGF-β from its latent form and modulation of various signals downstream of integrin-engagement, which participate in the non-canonical regulation of TGF-β signaling. TGF-β also induces expression of integrins, as well as their ligand extracellular matrix, generating an amplification loop. Furthermore, myriads of intracellular signaling molecules that associate with integrin engagement could noncanonically modulate TGF-β signals. The entire picture of this mutual regulation between integrin and the TGF-β pathways might be difficult to draw. Instead, this review intends to depict several critical aspects of this regulation, with examples from various types of fibrosis in different tissues to help understand the integrin-modulation of fibrogenesis, a critical clue for therapeutic approaches to fibrosis.

Skin fibrosis, in its mildest form, may present only a minor aesthetic problem, but in the most severe cases it can lead to debilitating pathologies of the skin, for example keloid and hypertrophic scars, and systemic sclerosis. In recent years, extensive basic research aimed at understanding the molecular mechanisms underlying fibrosis has revealed an impressive but baffling number of genes, molecules, and cell types that may contribute to this problem. However, one recurring and consistent theme in these studies is that inflammatory cells and their secreted mediators appear to be leading culprits in activating dermal fibroblasts to become fibrotic. This review will first describe the histology of normal versus fibrotic skin, and will also describe the process of wound repair, a primary cause of skin fibrosis. We will then focus on what is currently known about the molecular mechanisms underlying skin fibrosis, with particular attention paid to how inflammation contributes. Finally, current treatment strategies and emerging therapeutic targets will be discussed.

The anterior segment of the eye ball, i. e., cornea and conjunctiva, serves as the barrier to the external stimuli. Cornea is transparent and is a “window” of the light sense, while conjunctiva covers the sclera, the main part of the eyeshell. Fibrosis/scarring in cornea potentially impairs vision by the reduction of its transparency and the alteration of the regular curvature. Fibrotic reaction in conjunctiva is also of clinical importance because inflammatory fibrosis in this tissue affects the physiology of the cornea and also a problem of post-eye surgery. In this review, we discuss the topic that is quite critical in vision. Although, various growth factors have been considered to be involved in, focus was put on the roles of transforming growth factor β (TGFβ).

Sepsis, which is defined as a systemic inflammatory response syndrome that occurs during infection, is associated with several clinical conditions and high mortality rates. As sepsis progresses immune paralysis can become severe, leaving an already vulnerable patient ill equipped to eradicate primary or secondary infections. At present the predominant treatments for sepsis have not demonstrated convincing efficacy of decreased mortality. During sepsis, it has been observed that leptin levels initially increase but subsequently decline. A body of evidence has demonstrated that central or systemic leptin can beneficially regulate immune function. In this report expression of leptin and its receptor, signaling, and function on leukocytes will be reviewed. Furthermore, the effects mediated by central and systemic leptin during sepsis will be reviewed. Altogether, the ability of leptin to beneficially enhance inflammation and the host response during sepsis supports its use as a therapeutic agent, particularly during the latter phases of the syndrome.

Vitamin E regulation of disease has been extensively studied in humans, animal models and cell systems. Most of these studies focus on the α-tocopherol isoform of vitamin E. These reports indicate contradictory outcomes for anti-inflammatory functions of the α-tocopherol isoform of vitamin E, especially with regards to clinical studies of asthma and atherosclerosis. These seemingly disparate clinical results are consistent with recently reported unrecognized properties of isoforms of vitamin E. Recently, it has been reported that physiological levels of purified natural forms of vitamin E have opposing regulatory functions during inflammation. These opposing regulatory functions by physiological levels of vitamin E isoforms impact interpretations of previous studies on vitamin E. Moreover, additional recent studies also indicate that the effects of vitamin E isoforms on inflammation are only partially reversible using physiological levels of a vitamin E isoform with opposing immunoregulatory function. Thus, this further influences interpretations of previous studies with vitamin E in which there was inflammation and substantial vitamin E isoforms present before the initiation of the study. In summary, this review will discuss regulation of inflammation by vitamin E, including alternative interpretations of previous studies in the literature with regards to vitamin E isoforms.

Protein kinase C theta (PKC-) is a key kinase in mediating T cell receptor (TCR) signals. PKC- activated by T cell receptor (TCR) engagement translocates to immunological synapses and regulates the activation of transcriptional factors NF-κB, AP-1, and NFAT. These transcription factors then activate target genes such as IL-2. T cells deficient in PKC- display defects in T cell activation, survival, activation-induced cell death, and the differentiation into inflammatory T cells, both in vitro and in vivo. Since these effector T helper cells are responsible for mediating autoimmunity, selective inhibition of PKC- is considered a treatment for prevention of autoimmune diseases and allograft rejection.