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Novel Roles for Chemokines and Fibroblasts in Interstitial Fibrosis

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Novel Roles for Chemokines and Fibroblasts in Interstitial Fibrosis View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 54 (1998), pp. 2152–2159 BASIC SCIENCE - BIOCOMPATIBILITY Novel roles for chemokines and fibroblasts in interstitial fibrosis CORY M. HOGABOAM,MATTHEW L. STEINHAUSER,STEPHEN W. CHENSUE, and STEVEN L. KUNKEL Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA Novel roles for chemokines and fibroblasts in interstitial fibrosis. process is remarkably complex, involving the co-ordination Background. Regardless of its involvement in either wound of numerous types of cells and a myriad of soluble media- healing or excessive fibrosis, the interstitial fibroblast can now be considered an important early participant in inflammatory re- tors. The quest of researchers in this field has been to sponses. Although it is recognized that certain immune cells and characterize the precise chain of events in the fibrotic proinflammatory mediators are intricately linked to fibrotic dis- process in order to determine mechanisms through which ease, little is presently known about the manner in which these this process can be regulated, particularly when it becomes mediators and cells are orchestrated to a fibrotic finale. Experimental studies have shown that interstitial fibroblasts are capable of partic- deleterious as in a number of fibrotic diseases. However, ipating in an inflammatory response by promoting direct fibroblast- this task has been incredibly daunting in light of emerging to-immune cell communication and/or modulating the release of evidence that the fibrotic process is extremely complex and soluble mediators that are mutually recognized by both types of cells. appears to be dictated by a variety of biological networks. It Methods. Primary cultures of murine fibroblasts were recovered from either normal tissue or tissue undergoing a cell-mediated is apparent that excessive fibrosis follows inflammation, but inflammatory response. These stromal cells were assessed for the not all inflammatory events lead to excessive fibrosis. An expression of various cytokines and chemokines indicative of a type inflammatory response to infection or injury within most 1 or type 2 response. In addition, the fibroblasts were co-cultured tissues is typically characterized by the release of a myriad with mononuclear cells to assess the cell-to-cell communication. Results. Fibroblasts recovered from different cell-mediated of newly generated and preformed inflammatory mediators inflammatory responses demonstrated a dramatic alteration in by tissue resident immune (that is, macrophages and mast their cytokine profile. Fibroblasts recovered from the type 2 cells) and non-immune (that is, fibroblasts, epithelial and immune response produced high levels of monocyte chemotactic smooth muscle) cells. Two key functions of the soluble protein-1 (MCP-1), as compared to the normal fibroblasts and fibroblasts recovered from the type 1 lesion. Mononuclear cells mediators are to modulate the function of the resident cells co-cultured with fibroblasts induced a contact-dependent expres- and promote the infiltration of lymphocytes and phago- sion of elevated levels of chemokines, especially the macrophage- cytes. These concerted efforts ideally facilitate the destruc- derived MIP-1 alpha. Thus, both fibroblasts themselves and tion and/or clearance of the inflammatory stimulus. fibroblasts co-cultured with immune-inflammatory cells have the ability to participate in the maintenance of an inflammatory Upon reaching this goal, the final stage of the inflamma- response via the expression of chemokines. tory response involves the restoration of the tissue to its Conclusions. Our laboratory and others have addressed the role of original state. Clearly, the recruitment and tissue reparative chemotactic cytokines or chemokines in the fibrotic process, and stages must be closely regulated in organs such as the have demonstrated that fibroblasts are capable of modulating the activation of various immune cells that have been implicated in kidney, gut, lungs, and heart (and presumably the perito- fibrotic disease. In addition, the interstitial fibroblast is capable of neal membrane), as excessive tissue injury or over-exuber- regulating its own behavior within the interstitial environment via the ant tissue healing can severely disrupt the function of these expression of chemokines and chemokine receptors. Thus, novel organs. Whereas the fibroblast is blamed for the complica- strategies aimed at preventing fibrotic disease will likely need to address the early engagement of inflammatory cells by fibroblasts, tions of end stage or fibrotic disease, growing experimental and possibly modulate the ability of fibroblasts to generate and/or evidence suggest that this tissue resident cell is involved in recognize profibrotic signals supplied by chemokines. the inflammatory process at much earlier stages. For example, a number of experimental studies now suggest that interstitial inflammation and homeostasis is achieved, The fibrotic response is a critical component of tissue in part, by counter-regulatory actions of cytokines and restoration or healing following injury or infection. This chemokines. Therefore, the nature and consequences of the interactions between fibroblasts and immune cells such Key words: wound healing, inflammation, tissue repair, injury, fibrotic as macrophages/monocytes, T cells, mast cells, and eosin- disease, immune response. ophils become important aspects of the normal evolution of © 1998 by the International Society of Nephrology the immune response. 2152 Hogaboam et al: Chemokines and fibroblasts in fibrosis 2153 CLINICAL INTERSTITIAL FIBROTIC DISEASES cytokines are now commonly referred to as Th1- and Th2-type cytokines, as it is recognized that cells other than Interstitial diseases are inflammatory disorders that are T cells can generate IFN-g and IL-4 during immune typically characterized by excessive tissue injury and pro- responses in vivo. For example, natural killer cells are an gressive fibrosis, as exemplified in the pathology of glomer- important source of IFN-g while mast cells can generate ulonephritis, idiopathic fibrosis, and end stage sarcoidosis IL-4 [10]. In addition, macrophage derived IL-12 and IL-10 [1]. Although a growing list of inflammatory mediators more recently have been shown to exert prominent cross present in interstitial diseases includes cytokines, growth regulatory effects on Th cell cytokine profiles, and thus factors, prostanoids, eicosanoids and free radicals, little is have also been included in the Th cytokine profiles of currently known about the manner in which these media- Th1-type and Th2-type, respectively. tors initiate and sustain these complex diseases. Clinical With this background knowledge, models of prolonged and laboratory evidence suggest that fibrotic diseases result pulmonary inflammation were generated that predomi- when the tissue is unable to regulate the inflammatory nately exhibit either a Th1- or Th2-type cytokine profile process because of the persistence of one or several inflam- [11]. The intravenous administration of Sephadex beads matory signals [2]. Current clinical strategies directed at coated with purified peptide derivative (PPD) from myco- preventing fibrotic diseases through the nonspecific inhibi- bacteria into PPD-sensitized mice initiates the formation of tion of the inflammatory process with corticosteroid, cyclo- granulomatous inflammation that is driven by Th1-type phosphamide, and azathioprine treatments have been cytokines such as IFN-g, IL-2 and IL-12 [11]. The Th2-type largely unsuccessful, and are often associated with severe counterpart to this pulmonary inflammation model in side-effects [3]. The failure of the treatment strategies may initiated by the intravenous introduction of the parasite relate to the non-discriminating manner in which these antigen, Schistosoma mansoni egg antigen (SEA), and this drugs inhibit important modulatory factors involved in the model is driven by IL-4 and IL-5 [12]. Thus, the nature of inflammatory response. Accordingly, recent experimental the cytokine profile appears to be critical in the type of data suggest that the development of novel therapeutic inflammatory cells that are involved in the inflammatory strategies for interstitial fibrotic diseases should encompass stage and the magnitude of the tissue reparative stage. The specific modulators of the involvement of the fibroblast in Th1-type model is typified by the presence of mononuclear the inflammatory process. These studies strongly suggest cells such as lymphocytes and monocytes, while the Th2- that the fibroblast is not a bystander during inflammatory type model contains mononuclear cells, fibroblasts, and responses in the different involved tissue, but rather has a eosinophils. The relative importance of IFN-g and IL-4 to very specialized role in the recruitment and regulation of the development and the resolution of granuloma forma- immune cells that infiltrate the interstitial space. In addi- tion in the respective models was confirmed using adeno- tion, the balance between normal tissue repair and excess viral-based gene transfer [13] and gene knock-out mice collagen deposition appears to be dictated by the nature of [14]. These studies also confirmed that different Th-type the interaction between immune cells and fibroblasts dur- cytokines have cross-regulatory effects in these models of ing inflammatory conditions. chronic inflammation; however, it was apparent from these experiments
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