[Show abstract][Hide abstract] ABSTRACT: CD14+ peripheral blood monocytes can differentiate into fibroblast-like cells called fibrocytes, which are associated with and are at least partially responsible for wound healing and fibrosis in multiple organ systems. Signals regulating fibrocyte differentiation are poorly understood. In this study, we find that when added to human PBMCs cultured in serum-free medium, the profibrotic cytokines IL-4 and IL-13 promote fibrocyte differentiation without inducing fibrocyte or fibrocyte precursor proliferation. We also find that the potent, antifibrotic cytokines IFN-gamma and IL-12 inhibit fibrocyte differentiation. In our culture system, IL-1beta, IL-3, IL-6, IL-7, IL-16, GM-CSF, M-CSF, fetal liver tyrosine kinase 3, insulin growth factor 1, vascular endothelial growth factor, and TNF-alpha had no significant effect on fibrocyte differentiation. IL-4, IL-13, and IFN-gamma act directly on monocytes to regulate fibrocyte differentiation, and IL-12 acts indirectly, possibly through CD16-positive NK cells. We previously identified the plasma protein serum amyloid P (SAP) as a potent inhibitor of fibrocyte differentiation. When added together, the fibrocyte-inhibitory activity of SAP dominates the profibrocyte activities of IL-4 and IL-13. The profibrocyte activities of IL-4 and IL-13 and the fibrocyte-inhibitory activities of IFN-gamma and IL-12 counteract each other in a concentration-dependent manner. These results indicate that the complex mix of cytokines and plasma proteins present in inflammatory lesions, wounds, and fibrosis will influence fibrocyte differentiation.
[Show abstract][Hide abstract] ABSTRACT: Hypertrophic scar and keloids are fibroproliferative disorders of the skin which occur often unpredictably, following trauma and inflammation that compromise cosmesis and function and commonly recur following surgical attempts for improvement. Despite decades of research in these fibrotic conditions, current non-surgical methods of treatment are slow, inconvenient and often only partially effective. Fibroblasts from these conditions are activated to produce extracellular matrix proteins such as collagen I and III, proteoglycans such as versican and biglycan and growth factors, including transforming growth factor-β and insulin like growth factor I. However, more consistently these cells produce less remodeling enzymes including collagenase and other matrix metalloproteinases, as well as the small proteoglycan decorin which is important for normal collagen fibrillogenesis. Recently, the systemic response to injury appears to influence the local healing process whereby increases in Th2 and possibly Th3 cytokines such as IL-2, IL-4 and IL-10 and TGF-β are present in the circulating lymphocytes in these fibrotic conditions. Finally, unique bone marrow derived cells including mesenchymal and endothelial stem cells as well as fibrocytes appear to traffic into healing wounds and influence the healing tissue. On this background, clinicians are faced with patients who require treatment and the pathophysiologic basis as currently understood is reviewed for a number of emerging modalities.
[Show abstract][Hide abstract] ABSTRACT: Lower extremity ulceration is one of the serious and long-term diabetic complications rendering a significant social burden in terms of amputation and quality-of-life reduction. Diabetic patients experience a substantial wound-healing deficit. These lesions are featured by an exaggerated and prolonged inflammatory reaction with a significant impairment in local bacterial invasion control. Experimental and clinical evidences document the deleterious consequences of the wound's pro-inflammatory phenotype for the repair process. From a biochemical standpoint, hyperinflammation favours wound matrix degradation, thus, amplifying a pre-existing granulation tissue productive cells' invasiveness and recruitment deficit. Tumour necrosis factor perpetuates homing of inflammatory cells, triggers pro-apoptotic genes and impairs reepithelialisation. Advanced glycation end-products act in concert with inflammatory mediators and commit fibroblasts and vascular cells to apoptosis, contributing to granulation tissue demise. Therapeutic approaches aimed to downregulate hyperinflammation and/or attenuate glucolipotoxicity may assist in diabetic wound healing by dismantling downstream effectors. These medical interventions are demanded to reduce amputations in an expanding diabetic population.
International Wound Journal 11/2008; 5(4):530-9. DOI:10.1111/j.1742-481X.2008.00457.x · 2.15 Impact Factor
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