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Tissue scarring due to abnormal matrix remodeling is an important cause of organ failure, which is a leading cause of morbidity and mortality. Current studies have fo cused on determination of the molecular basis of controlled wound healing and uncontrolled tissue scarring. Scarless repair is a unique feature of fetal wounds in early gestation. Our understanding of the molecular basis of fetal response during wound healing may represent a paradigm to modulate incomplete and/or excessive healing (tissue scarring) to an ideal scarless healing. Once the fetal microenvironment that steers scarless wound healing is known, attempts to create a similar artificial environment to modulate abnormal tissue scarring could be accomplished. This brief review addresses the pathogenesis of wound healing and its relevance to tissue scarring.

Recent studies of cytokines, chemokines, adhesion molecules and growth factors have enhanced our understanding of molecular mechanisms of leukocyte trafficking and their activation in the inflammatory phase of various renal diseases. Interactions between infiltrated inflammatory cells and resident renal cells are actively involved in the pathogenesis of phase-specific renal disorders. Furthermore, a number of proinflammatory and fibrogenic cytokines, chemokines and growth factors exert their biological activities through their receptors expressed on resident renal cells, to induce inflammatory responses that eventually lead to the development of fibrosis in various renal diseases. Thus, measuring the levels of certain proinflammatory molecules might provide useful information about the inflammatory state of the diseased kidney and could have clinical importance and significance. The selective intervention of some of these molecules might have the therapeutic potential to modulate renal inflammatory responses, and thereby could alter disease progression. Despite the apparent redundancy, accumulating evidence supports this possibility. In this chapter, we will briefly summarize the specific roles of certain proinflammatory molecules in the pathogenesis of various human and experimental renal diseases.

Renal fibrosis usually indicates irreversible tissue damage, irrespective of the initial cause. Thus, it is most relevant to understand mechanisms leading to renal fibrosis. Oxidative stress has emerged as an important factor contributing to tissue damage, and oxidative stress is enhanced in a variety of inflammatory disease states relevant for the kidney. It is therefore the purpose of this chapter to discuss the role of oxidative stress in the development of renal fibrosis. Inflammation is generally associated with enhanced oxidative stress, and since multiple factors contribute to inflammation [such as cytokines (e.g., interleukin-6, tumor necrosis factor α), infection, ischemia reperfusion injury, homocysteine, advanced glycation end products, atherogenic lipoproteins, or angiotensin II], multiple factors can cause enhanced oxidative stress. Here we will focus on the role of atherogenic lipoproteins, particularly oxidized low density lipoproteins, and the activated renin angiotensin system, for several reasons: firstly, these factors are well characterized as proinflammatory and as stimulators of superoxide-generating enzymes; secondly, the contribution of these factors to tubulointerstitial fibrosis has frequently been described; and thirdly, we already possess pharmacological tools to efficiently lower their activity. Thus, this chapter highlights the interplay of oxidative stress, atherogenic lipoproteins, and the renin angiotensin system in the pathophysiology of renal fibrosis and discusses potential treatment options.

Nuclear factor-κB (NF-κB) comprises a family of transcription factors. They are thought to have a central role in the expression of genes involved in cell mobilization, cell proliferation and cell differentiation, and, hence, in inflammation, repair and fibrosis processes. In particular, NF-κB activation appears to drive a number of inflammatory diseases of the kidney and their progression to end-stage renal failure. Thus, targeting NF-κB activation would lead to the development of new pharmaceutical compounds that would provide novel treatment for these diseases.

Hypercholesterolemia is a common feature of nephrosis or uremia. Dietary hypercholesterolemia aggravates the renal injury in experimental focal segmental glomerulosclerosis (FSGS). Hypercholesterolemia is mainly due to increased level of low-density lipoprotein (LDL). Accumulation of apolipoprotein B-containing lipoproteins or LDL is frequently shown in the diseased human glomeruli. Furthermore, oxidized LDL (Ox-LDL) has been demonstrated in the lesions of FSGS or mesangial areas. Ox-LDL in the diseased glomeruli could recruit the circulating monocytes leading to the accumulation of macrophages and subsequent foam cell formation. Increased release of macrophage-derived products could produce an altered mesangial cell matrix biosynthesis. In cultured mesangial cells, LDL is susceptible to oxidative modification, and stimulates mRNA and/or protein expression of α1(I), α1(III) and α1(IV) collagen, laminin, fibronectin and transforming growth factor-β1 (TGF-β1). LDL also upregulates plasminogen activator inhibitor-1 (PAI-1), urokinase-type plasaminogen activator (uPA) and tissue-type plasminogen activator (tPA) expression after prolonged incubation times in mesangial cells. LDL-induced plasminogen activator inhibitory activity was greater than plasminogen activator activity. LDL increased protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity as well as bioactive TGF-β secretion in cultured mesangial cells. LDL-induced α1(IV) collagen, PAI-1 or fibronectin overexpression in mesangial cells was abrogated by inhibition or downregulation of PKC or by administration of anti-TGF-β suggesting that LDL stimulates mesangial matrix protein expression through induction of PKC or TGF-β. Altogether, these effects of LDL on altered regulation of the mesangial matrix synthesis/degradation might have a pathophysiological function in the pathogenesis of glomerulosclerosis.

Progressive renal disease is associated with the development of fibrosing lesions not only in the glomerulus, but also in the interstitial and vascular compartments of the kidney, in a process that involves the mesenchymally derived, phenotypically similar, mesangial cell, myofibroblast and vascular smooth muscle cell. The similarities in the pathogenesis of all three processes means that the search for rational treatment strategies for any one may be of universal benefit to the others.

Potential therapeutic strategies target fibrosis both indirectly and directly. Indirect therapies alter the environment the kidney operates in such as by controlling blood pressure, hyperlipidemia and hyperglycaemia. As our understanding of the mechanisms of fibrosis increase, we are developing more direct treatment strategies that target the vasoactive mediators, growth factors and cell signaling pathways that regulate renal fibrogenesis. Finally attempts to increase collagen degradation and maintain blood supply are likely to reduce the damage resulting from aberrant collagen synthesis.

The continuing advances in cellular and molecular biology mean that we are becoming more aware of how cells interrelate with each other and their environment. Measures that specifically interfere with fibrosis can therefore be expected to improve prognosis not only in progressive renal failure but also in progressive fibrosing diseases in many other organs.

Progressive renal disease is associated with the concurrent development of fibrosing lesions not only in the glomerulus, but also in the interstitial and vascular compartments of the kidney (Fig. 1). Though attention is usually directed separately to the three processes—glomerulosclerosis, tubulointerstitial fibrosis and vascular sclerosis—all three eventually occur and the fundamental pathology is similar.

Renal fibrosis or sclerosis refers to the replacement of renal parenchyma with connective tissue, in a process that resembles the generalised chronic inflammation that occurs elsewhere. Initiating injury, recruitment of inflammatory cells (neutrophils, macrophages, T-cells), generation and release of profibrotic growth factors, proliferation and matrix synthesis, and finally matrix remodelling are the sequential but overlapping events. Increases in both the number and activity of matrix producing cells is responsible for matrix deposition, with the balance between this and remodelling determining the extent of scarring.

Fibrogenesis is essential for infarct healing and affects ventricular remodeling, one of the most important prognostic factors after myocardial infarction. Fibrogenesis is initiated by a variety of cytokines and growth factors produced by activated macrophages and inflammatory cells during the initial inflammatory phase. Fibroblasts that proliferate and infiltrate into the infarct zone are transformed into myofibroblasts, which express a variety of extracellular matrix (ECM) components that reconstruct the ECM in the infarcted myocardium. Following the inflammatory phase, fibrogenesis occurs prominently in the granulation tissue around the necrotic myocardium. Fibrillar collagens play major structural roles in infarct fibrosis. In addition to fibrillar collagens, basement membrane components of the ECM, type IV collagen, perlecan proteoglycan and laminin, appear in the infarct zone and also contribute to infarct ECM reconstruction. Other glycoproteins and proteoglycans are also expressed in the infarct zone and function in ECM reconstruction through their biological activity. Matricellular proteins modulate ECM reconstruction through paracrine and autocrine processes. Among various mediators of ECM homeostasis, transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) and angiotensin II function importantly in promoting infarct fibrogenesis. Stretching of the myocardial wall and hypoxia are physiological factors that are specific to myocardial infarction and stimulate infarct fibrogenic processes through enhancing the levels of the fibrogenic mediators. Intercellular fibrosis also occurs in the noninfarct zone and TGF-β1 and angiotensin II promote this fibrosis. Reperfusion and pharmacological intervention may modulate infarct fibrogenic processes and limit ventricular remodeling.

Excessive deposition of extracellular matrix proteins during aging leads to a progressive reduction of myocardial and arterial compliances. The increased cardiovascular stiffness may in turn determine a reduced capacity of the aged heart to respond to stressful situations. Our knowledge on the biology of extracellular matrix during aging derives mainly from observations made in animal models. The age-dependent accumulation of collagen in the heart is not related to an increased synthesis, but rather to a reduction of its degradation by specific matrix metalloproteinases and to an increased cross-linking of mature collagen that renders it more resistant to degradation. Specific pharmacological treatments are currently in use to limit or even reverse the progressive stiffening of the arteries and myocardium.

Athero-arteriosclerosis is the most common age-related pathology. Frequent manifestations are thrombo-embolic incidents, mostly of the coronary circu-lation and heart insufficiency resulting from an increased work load on the heart as a result of progressive increase of peripheral resistance and loss of contractile cardiac muscle fibers. Major advances made during the second half of the XXth century in the cell-biological-biochemical description of the underlying mechanisms led to increasing success of prevention, treatment and, displacing the pathological consequences to later years of life. This will result in the XXIst century in a new emphasis on the importance of biochemical and structural alterations of the large vessel wall, mainly responsible for the increasing risk of heart failure due to overload. This process, arteriosclerosis, can best be described by the progressive modification of the macromolecular composition of the vascular extracellular matrix. This is partially the result of a progressive shift in the phenotype of vascular smooth muscle cells and partially the result of postsynthetic modifications of matrix macromolecules. We shall summarize some of the most important findings made over the years in a number of laboratories concerning this process.

Hepatic stellate cells play essential roles in the pathogenesis of liver fibrosis. Transformation of stellate cells from the vitamin A-storing pheno-type to the “myofibroblastic” one closely correlates to hepatic fibrogenesis during chronic liver diseases. Understanding the molecular mechanisms of stellate cell activation have made a great progress, in particular, in the field of intracellular signal transduction of transforming growth factor-β and platelet-derived growth factor and collagen gene expression. Accumulation of the information on the stellate cell activation would shed light on the establishment of a novel therapeutic strategy against fibrotic liver diseases.