Med Electron Microsc (2004) 37:141–148 DOI 10.1007/s00795-004-0255-2
© The Clinical Electron Microscopy Society of Japan 2004
REVIEW Abdallah Azouz · Mohammed S. Razzaque Moussa El-Hallak · Takashi Taguchi
Immunoinflammatory responses and fibrogenesis
Received: January 20, 2004 / Accepted: May 18, 2004
Abstract In response to injury, tissues adjacent to the damaged area initiate a cascade of inflammatory and matrix remodeling events that are necessary to restore tissue integrity and function. The typical features of such healing effects in adult mammals are deposition of matrix proteins, which mature to scar tissues. In general, the wound healing response demonstrates certain commonalities across organs, but there are also organ-specific mechanisms. Such organ-specific controlled healing and uncontrolled tissue scarring are partly determined by the bioactivities of resident cells and local microenvironments, which are influenced by multiple factors, including the presence of specific types of cytokines (Th1 and Th2), chemokines, growth factors, cell–cell interaction, and reorganization of matrix proteins. In this article, we briefly present the relevance of Th1 and Th2 responses and the significance of interactions between matrix-producing cells and inflammatory cells during granuloma tissue and scar tissue formation. Key words Cytokines · Cell–cell interaction · Extracellular matrix · Fibrogenesis
Introduction Tissue repair is a complex process that begins with delicate molecular interactions among various types of cells that A. Azouz Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA M.S. Razzaque (*) Department of Oral and Developmental Biology, Forsyth Institute, Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115, USA Tel. ⫹1-617-892-8307; Fax ⫹1-617-892-8303 e-mail: mrazzaque@forsyth.org M.S. Razzaque · T. Taguchi Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan M. El-Hallak Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
include activation of platelets and induction of the coagulation cascade; this is followed by the release of a number of soluble factors essential for the recruitment of leukocytes and activation of resident cells. The healing process is primarily regulated by fibroblast through synthesizing or organizing matrix components, predominantly fibrillar collagens.1–3 Fibroblasts respond to altered microenvironmental signals by facilitating recruitment and retention of bone marrow-derived immune effector cells, and by cell–matrix or cell–cell interactions, to regulate synthesis and degradation of matrix proteins. A controlled healing response results in minimal scarring and in preservation of normal structural and functional abilities. Dysregulation at any stage of this complex process may lead to extensive tissue scarring, with loss of physiological functions. Recent studies have increased our understanding of fibroblast activation, differentiation, proliferation, and eventual secretion of a wide range of inflammatory and matrix-remodeling molecules during tissue scarring. In addition to fibroblastic cells, studies have documented an important role of inflammatory cells in the pathogenesis of a number of chronic inflammatory diseases, including rheumatoid arthritis, nephritis, scleroderma, and granuloma formation in schistosomiasis. Inflammatory cells, including lymphocytes and macrophages, not only release cytokines, chemokines, and growth factors during the immunoinflammatory phase of the disease but also regulate the fibrogenic phase of the disease process through direct interaction with fibroblasts.4,5 This interaction between fibroblasts and inflammatory cells can further increase the production of proinflammatory and profibrogenic molecules, thus resulting in the development of fibroproliferative lesions.6,7
Th1 and Th2 responses The type 1 [Th1; including interferon (IFN)-γ and interleukin (IL)-2] and type 2 [Th2; including IL-4, IL-5, IL9, IL-10, and IL-13] cytokines profiled during immune response were initially revealed in mice using a panel of T
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helper cell clones. The functional diversity of these cytokines is thought to be important in dictating different phases of immunoinflammatory responses. Th1 cytokines are mostly involved in cell-mediated immunity associated with autoimmune disorders and allograft rejection, whereas Th2 cytokines are mostly involved in mediating allergic inflammation and chronic fibroproliferative disorders, including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis.8 In most fibroproliferative disorders, both Th1 and Th2 responses appears to be present, whereas inflammatory events in response to the initial inciting agent trigger a Th1 response. The subsequent host reactions to the foreign particles and the chronicity of the disease process are usually driven by Th2 responses. This latter response mostly regulates stromal cell/fibroblast activation, proliferation, myofibroblastic differentiation, and matrix accumulation with eventual tissue scarring.1–3 Although recent research has enhanced our understanding about certain aspects of Th1 and Th2 responses during formation of granulomatous and fibrogenic lesions, it has at the same time raised a few important questions. In mice with schistosome infection, there are dynamic changes in the prevailing Th1 and Th2 cytokine responses. In schistosomiasis, fibrosis is associated with the granulomatous response to parasite eggs trapped in the liver. The initial period of 4–5 weeks of infection is largely driven by the Th1 cytokine.9,10 The Th1 response in the early phase of the infection is initiated by higher numbers of IFN-γsecreting CD4⫹ and CD8⫹ cells in the spleen and lymph nodes of the infected mice.11 The Th2 cytokine responses supersede the early Th1 responses during the commencement of egg laying (4–5 weeks of infection).10 The predominance of Th2 responses by 7–8 weeks of infection is associated with decreased Th1 responses.10–12 Granuloma formation by schistosomal egg antigen (SEA) is mostly by the major histocompatibility complex (MHC) class IIrestricted phenomenon, with the involvement of CD4⫹ T helper (Th) lymphocytes. Studies have shown that SEAinduced granuloma fail to develop in athymic mice13 or mice lacking αβ-expressing T cells, MHC class II molecules, or recombination-activating gene 1(Rag-1).14,15 Cloned specific Th1-type lymphocytes are capable of mediating granuloma formation, which are Ag specific, MHC restricted, and local DTH (delayed-type hypersensitivity) reactions; studies have shown that in vivo egg-associated granuloma formation can be mediated by monoclonal SEA-specific Th1 cells. It has been suggested that a small T-cell fraction sensitized by SEA determinants may be sufficient to elicit the hepatointestinal granulomatous inflammation associated with schistosomiasis,16 which is consistent with the notion that the development of these lesions depends on the proinflammatory CD4⫹ Th1-type cells producing IFN-γ and IL-2. The kinetic analysis of cytokine production by SEAstimulated mesenteric lymph node (MLN) cells has provided further evidence of Th1-dominated responses in egg-induced immunopathology. These studies showed that in the low-pathology BL/6 (H-2b) mice an initial brief Th1type response is promptly replaced by a sustained Th2-type response,17 whereas in the high-pathology C3H (H-2k) mice
the Th1 response (IFN-γ and IL-2) persists alongside the Th2 response (IL-4, IL-10, and IL-13).18 Moreover, immunized schistosome-infected, low-pathology, and Th2-biased BL/6 mice with SEA resulted in a striking reversal in cytokine production toward a Th1-dominant profile, as detected in the MLNs, spleens, and granulomatous lesions. Studies have also shown that mice tolerant to schistosome eggs have elevated Th1 responses with diminished Th2 responses and reduced antiegg antibody during schistosome infection; hence, these effects are detrimental to the host response. However, the detection of IL-4 and IL-5 production in response to SEA during peak granuloma formation after 8weeks of infection suggests a possible Th2 response. The Th2 cytokine responses by eggs is evident as cells recovered from naive mice injected with isolated schistosome eggs induced the secretion of Th2 cytokines.19 Conversely, a number of other studies using mice with targeted mutations in the J(H) locus (the phenotype results in the absence of B cells and of antibody production, thus lacking Th2dependent signals emanating from B cells) have suggested that even in the absence of Th2 components, egg-induced granulomatous lesions can form,20 and that IFN-γ and IL-4 can both positively or negatively influence the formation of granulomas or can be essentially irrelevant for the development of these lesions.21 Although studies have been able to define the cytokine profile in various stages of egg-induced granuloma formation in schistosomal infection, further studies are needed to determine how the molecular interactions of these cytokines in different phases of the disease process eventually develop granulomatous lesions. The pattern of immunoinflammatory mediators during the early phase of many infectious organisms shows heterogeneous response in different mice strains: for example, C57BL/6J mice tend to express Th1 cytokines (IFN-γ, IL-2) and BALB/c mice tend to express Th2 cytokines (IL-4, IL5) in response to identical infectious agents such as Leishmania major.22 It is interesting to note that bleomycinsusceptible mice, such as the C57BL/6J and C3H/HeN strains, generate predominantly Th1 responses when challenged with soluble antigens or infectious agents, whereas the “fibrosis-resistant” BALB/c strain tends to produce Th2 cytokines in response to similar stimuli.23 It appears likely that defining a disease process by various phases and stages in terms of the predominant cytokine profile may be useful in developing a phase-specific therapeutic strategy.
Cell–cell interaction Cell–cell interaction is an important determinant factor that not only regulates the microenvironment but also affects fibrogenesis (Fig. 1). CD40 is an important molecule that helps in fibroblast activation.24 CD40 is a 45- to 50-kDa type I membrane glycoprotein; it is the cognate receptor for CD40 ligand (CD154), which is a member of the tumor necrosis factor family.25 In addition to antigen-presenting cells (B cells and dendritic cells),25 nonmarrow-derived cells
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Macrophage
MHC2
CD80/ CD86
IL-1 TNF-a TGF-b1 PDGF
CD28
CD40/CD40L TCR CD4
TH1 and TH2 cytokines
T cell
CD40/CD40L
Fibroblast
Transdifferentiation
TGF-b1
MCP-1 TGF-b1 CTGF IL-4 IL-13 HSP47 MMPs TIMPs
Matrix remodeling
Healing responses
P
Myofibroblast Fig. 1. Schematic diagram showing possible cellular interactions during fibrogenesis. There are additional factors that may play a role during fibrogenesis, but to make the diagram simple, we have included only a limited number of molecules that are relevant to this article. MHC2, major histocompatibility complex, class II molecules; TCR, T-
cell receptor; IL-1, interleukin 1; TNF-α, tumor necrosis factor-alpha; MCP-1, monocyte chemoattractant protein 1; TGF-β1, transforming growth factor beta-1; PDGF, platelet-derived growth factor; CTGF, connective tissue growth factor; HSP47, heat shock protein 47; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase
including fibroblasts and keratinocytes also express CD40.26 These cells interact with CD40 ligand-expressing T cells,25 mast cells,25 and activated platelets.27 Fibroblasts express CD40 and respond to CD40 ligation by increasing the expression of intercellular adhesion molecule 1 (ICAM) and vascular cell adhesion molecule 1 (VCAM),28 thus producing inflammatory mediators.29,30 Human fibroblasts stimulated with CD40 ligand not only become activated but also induce synthesis of IL-1, IL-6, and IL-8, cyclooxygenase-2, prostaglandins, and hyaluronate.29–31 IFN-γ has the ability to induce expression of CD40 by human fibroblasts in vitro.26,29,30 These results are in accord with in situ data that show CD40 expression is significantly higher in acutely inflamed tissues as compared with noninflamed tissues.30 Lung fibroblasts express low levels of CD40, with few CD40 ligand (CD40L)-expressing cells in and around them. During tissue injury, platelets are thought to initiate the inflammatory phase of the healing process by engaging fibroblast CD40 via their surface/secreted CD40L. Similarly, T cells and mast cells migrate into the injured site and interact with fibroblasts through CD40L. This process induces fibroblasts to activate, proliferate, and produce cytokines and matrix proteins that eventually lead to wound healing.
Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune system.32 Studies have shown that CD40–CD40L interaction plays an important role in the pathogenesis of immune-mediated glomerulonephritides, which eventually develop renal fibrosis. In experimental models of lupus nephritis, anti-CD40L antibodies ameliorate nephritis even when administered after the onset of the disease process.33 Recent studies have demonstrated the in vivo role of CD40–CD40L interactions during chronic inflammation, and subsequent tissue scarring. Blocking CD40–CD40L in vivo by administering anti-CD40L antibody (MR1) substantially reduced pulmonary inflammation and fibrosis in C57BL/6 mice irradiated with a single dose of 15 Gy ionizing radiation to the thorax.34,35 These studies support the concept that the interaction of fibroblasts with such inflammatory cells such as T cells through the CD40– CD40L system is one of the early events that may eventually regulate the development of fibroproliferative lesions. The interaction of T cell with fibroblast is a complex process, and before any such interaction, T cells must be activated. T cells not only require a signal via the T-cell receptor (TCR) but also involve costimulatory signals to be functionally active.36 CD28 is a molecule that is constitu-
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tively expressed on the cell surface of T cells, and the interaction of CD28 with its ligands, CD80 and CD86, play a central role in providing costimulatory signals for T-cell activation.37,38 The CD28-mediated costimulation enhances T cell proliferation, survival, and cytokine production.36 In addition to the matrix-producing fibroblastic cells, a potential role for T cells has been suggested in fibrogenesis. Intratracheal administration of bleomycin into CD28deficient mice resulted in less fibrotic changes in the lung, whereas adoptive transfer of CD28-positive T cells from wild-type mice resulted in severe fibrotic changes in the lung of the CD28-deficient mice. It appears probable that the CD28-mediated T-cell costimulation and subsequent regulation of proinflammatory and profibrogenic molecules play an important role in fibrogenesis. Thus, manipulation of the CD28-mediated costimulation has therapeutic potential in modulating fibrogenic responses.39
Effects of cytokines on fibrogenesis TNF-α is one of the important cytokines that has pleiotropic effects on the inflammatory phase of various fibrotic diseases and are primarily derived from mononuclear cells. The expression of TNF-α appears to be significantly elevated in bleomycin-induced pulmonary fibrosis; blocking the bioactivities of TNF-α resulted in an attenuation of parenchymal cellularity, reduced alveolar septal thickening, decreased structural damage, and caused an overall reduction in fibrotic changes in the lungs.40,41 The important role of TNF-α in pulmonary fibrosis has been further substantiated by demonstrating fibrogenic changes in the lung of Sprague–Dawley rats that were genetically modified to over-express TNF-α in their lungs.42 However, in vivo upregulation of TNF-α does not always exert similar biological effects. TNF-α has been detected in many immunoinflammatory diseases that resolve without producing tissue scarring,43,44 yet in a number of diseases, upregulation of TNF-α is linked with fibroproliferative disorders.45 The mechanism of such diverse effects of TNF-α in various disease processes remains unclear, and this is an active field of research.42 The IL-1 family of cytokines consists of two agonists, IL1α and IL-1β, and one antagonist, IL-1 receptor antagonist (IL-1ra).46 Both the isoforms of IL-1 exert similar biological functions through binding with their receptors on target cells.46 Binding of IL-1 to its receptor leads to the activation of NF-kB to induce genes encoding for cyclooxygenase, adhesion molecules, cytokines, nitric oxide synthase (NOS), acute-phase proteins, and chemokines.47 The combination of these factors play a role (directly or indirectly) in the development of fibroproliferative lesions. Moreover, both IL-1α and IL-1β have the ability to induce the expression of fibrillar collagens (type I and III), glycosaminoglycans, and fibronectin by fibroblasts, and basement membrane collagen (type IV) by epithelial cells. Additionally, IL-1 exerts mitogenic effects on fibroblast through the expression of platelet-derived growth factor (PDGF) and its receptor
(alpha) on fibroblasts. Furthermore, IL-1α and IL-1β can serve as an early mediator of chronic inflammation and tissue scarring by inducing the production of a number of fibrogenic cytokines and chemokines (by fibroblasts). It has been demonstrated that transient expression of IL-1 using an adenoviral vector may lead to progressive fibrosis possibly by facilitating increased bioactivities of IL-6 and TNF-α, PDGF, and transforming growth factor (TGF-β1).48 This finding suggests an important in vivo role of IL-1 in the initiation and propagation of fibroproliferative responses.48 In addition to the inflammatory effects, IL-1 is also involved in matrix remodeling by facilitating production of proteolytic enzymes, such as matrix metalloproteinase (MMP-1), gelatinase, and plasminogen activator. IL-1ra is a naturally occurring inhibitor of IL-1 binding to its receptor. A dynamic interaction and balance between agonists and receptor antagonist influences the bioactivities of IL-1. A wide range of cells expresses IL-1ra and competitively attenuated the effects of IL-1 both in vitro and in vivo.46 The exogenous administration of IL-1ra has been shown to attenuate pulmonary fibrosis in bleomycin- or silica-treated animals.49 However, the exact mechanism of such attenuation of bleomycin- or silica-induced fibrosis is not clear, as the experiments did not provide the information of endogenous IL-1ra activities. This consideration may be of clinical importance given that the level of IL-1ra has been found to be significantly elevated in patients with IPF and sarcoidosis;50 a tenfold-higher level of IL-1ra has been detected in BALF in the patients with sarcoidosis and IPF,50,51 Also, the expression of IL-1ra was significantly increased in lung tissues of IPF patients as compared with normal lung tissues.51 Recently, an important role of IL-12 has been suggested in fibrotic disorders. IL-12 (IL-12p70) is a heterodimer composed of two disulfide-linked subunits of p35 and p40. Association of IL-12p35 and IL-12p40 subunits forms the bioactive heterodimer of IL-12p70.52,53 IL-12 is a key cytokine that induces Th1 response and acts mainly on T and natural killer (NK) cells. The bioactivities of IL-12 require interaction of the IL-12p35 and IL-12p40 subunits with the β1- and β2-chain of IL-12 receptors.54 Kikawada et al.55 showed that IL-12 deficiency in MRL-Faslpr mice delayed the onset of nephritis and other systemic pathology. In schistosomiasis, fibrosis is associated with the granulomatous response to parasite eggs trapped in the liver. Intraperitoneal administration of IL-12 with eggs prevents subsequent pulmonary granuloma formation on intravenous challenge with eggs.56 Moreover, sensitization of eggs with IL-12 partly inhibited granuloma formation and significantly reduced formation of tissue fibrosis that was induced by Schistosoma mansoni worms.56 Both these studies are interesting and reinforce the importance of cytokine profiling in determining the natural course of immune/inflammatory responses and disease phenotype that can either undergo resolution or progression to tissue scarring.57,58 Studies have demonstrated IFN-γ has the ability to suppress fibrogenic effects, possibly by attenuating the production of matrix proteins.57,58 INF-γ differentially regulates the expression of PDGF, ICAM-1, VCAM-1, and stromelysin 1
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by fibroblasts. The in vivo administration of IFN-γ resulted in less matrix accumulation in experimental mouse models of fibrosis.57 Furthermore, recent studies have shown that IL-12 attenuates bleomycin-induced pulmonary fibrosis partly by inducing IFN-γ.61 The therapeutic administration of IFN-γ to patients with systemic sclerosis or IPF for 1 year has resulted in improved pulmonary function.62,63 A less inflammatory response to intratracheal bleomycin exposure in IFN-γ(⫺/⫺) mice was associated with low mortality when compared with wild-type C57BL/6J mice.23 IFNγ has been shown to suppress collagen production in vitro by fibroblasts, possibly by suppressing TGF-β expression, a cytokine that induces matrix synthesis and accumulation.64,65 In the Schistosoma-induced mouse model of granulomatous lesion, administration of IFN-γ or IL-12 decreased the granulomatous responses, suggesting antifibrotic effects of these cytokines.56 Earlier studies showed that, in bleomycinsusceptible mouse strains, repeated administration of IFN-γ alone, or in combination with either poly-ICLC (polyinosinic-polycytidylic acid complexed with poly-llysine) or with IL-12, can induce IFN-γ and retard pulmonary fibrosis.66 It appears likely that chronic administration or pharmacological induction of certain cytokines, including IFN-γ, and IL-12 may serve to decrease the fibrotic activities in scarring diseases. Similarly, in a recent study, an antifibrotic effects of IFN-α has been demonstrated in an experimental model of hepatic fibrosis. For instance, IFN-α treatment of transgenic mice harboring the alpha 2(I) collagen gene promoter sequence resulted in delay in the progression of carbon tetrachloride-induced hepatic fibrosis, possibly by antagonizing the effects of TGF-β-induced transcription of collagen synthesis.67 In addition to the Th1 cytokines, an important role of certain Th2 cytokines has been demonstrated in various fibrotic diseases. Although the results are not always conclusive and further studies are needed to clarify certain issues, one of the cytokines shown to be involved in the fibrogenic process is IL-4. In contrast to some of the Th1 cytokines, Th2-type cytokines, including IL-4, promote fibroblast-derived matrix production.68 IL-4 acts as a chemotactic factor for fibroblasts and may induce fibroblast proliferation. An increased expression of IL-4 has been documented in various human and experimental fibrotic diseases involving skin, kidney, and ocular tissues.69 Interestingly, pulmonary expression of IL-4 in transgenic mice has shown very little or no fibrosis, whereas renal fibrosis has been documented in IL-4 in overexpressing mice, suggesting tissue-specific in vivo effects.69,70 Similarly, a recent study using IL-4-deficient (knockout) mice found no significant changes in the level bleomycin-induced pulmonary fibrosis; no such difference was noted when the studies were performed using IL-4-overexpressing (transgenic) mice.71 Recent studies have found that in addition to the IL-4, another Th2 cytokine, IL-13, plays an important role in the fibrogenic events of chronic immunoinflammatory diseases.72 Increased expression of IL-13 has been documented during schistosome infection, and the expression levels of IL-13 were almost 100 fold more than the expression of IL4.73 Interestingly, both IL-4 and IL-13 exert part of their
biological activities through the IL-4Rα chain. Similar to IL-4 and TGF-β1, IL-13 has a similar ability to induce type I and III collagens by fibroblastic cells.74 The phenotypes of IL-13 transgenic mice have demonstrated airway epithelial cell hypertrophy, mucous cell metaplasia, the hyperproduction of neutral and acidic mucus, and subepithelial airway fibrosis.75 The soluble IL-13 receptor (sIL13Rα2-Fc)*fusion protein has shown to successfully block fibrogenic effects of IL-13.73 IL-13-mediated hepatic fibrosis dramatically increased in the absence of IL-13Rα2, despite the fact that the production of local Th2 cytokine reduced significantly, suggesting an important decoy function for IL-13Rα2 during the development of Th2 cytokinemediated fibroproliferative lesions.76 These studies suggest the profibrotic effects of IL-13 on collagen homeostasis. However, not all Th2 cytokines are fibrogenic. IL-10 is a naturally produced cytokine that downregulates the inflammatory responses. When IL-10 knockout (KO) mice were inoculated with an avirulent parasite strain (ME-49), an intracellular protozoan, Toxoplasma gondii, high mortality has been documented in KO mice within the first 2 weeks of the infection with no apparent changes in parasite proliferation. The high mortality in the IL-10 KO mice was associated with extensive hepatic damage; an increased serum level of IL-12 and IFN-γ was detected in the infected KO mice, as were the levels of mRNA for IFN-γ, IL-1, TNF-α, and IL-12 in lung tissue.77 Furthermore, in vivo administration of IL-10 reduced the hepatitis C virus (HCV)induced hepatocellular injury and subsequent fibrogenic responses.78 IL-10 has the ability to downregulate the production of proinflammatory cytokines, such as TNF-α, IL-1, IFN-γ, and IL-2 from T cells. Endogenous IL-10 reduces the intrahepatic inflammatory response and limits hepatotoxicity in experimental models of liver injury.78 Further study will determine the molecular interactions and clinical potentials of IL-10. Among the matrix-regulating molecules, transforming growth factor (TGF)-β1 is one of the most extensively studied molecules. The fibrogenic role of the TGF-β1connective tissue growth factor (CTGF) pathway in various tissues and organs has been detailed in various recent reviews; therefore, we do not elaborate here. Recent studies have shown that higher TGF-β1 bioactivities are not always present during the development of fibroproliferative lesions. In mice lacking the hyaluronic acid (HA) receptor, CD44 has shown increased fibroproliferative responses following bleomycin treatment, despite lesser TGF-β1 bioactivities.79 In an interesting study, Kolb and coworkers examined the biological significance of the induction of TGF-β1 expression in the lungs of both fibrosis-prone and fibrosis-resistant mice strains and found that the fibrosisresistant Balb/c mice have significantly less fibrotic change even though these mice have higher levels of TGF-β1 expression, compared to sensitive C57BL/6 mice.80 This study suggests that differences in the expression of TGF-β1 cannot always determine the extent and susceptibility of fibrosis. The differential changes of TGF-β1 responses in these mice were not due to their inability to respond to TGF-β1 because primary fibroblasts isolated from fibrosis-resistant
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Balb/c mice have demonstrated similar collagen-synthesizing abilities following TGF-β1 treatment.80 The difference in susceptibility in developing fibrosis in these mice strains may be caused by genetic differences. A role of similar genetic influence has been suggested in human fibrotic diseases. For instance, although pulmonary fibrosis is triggered by diverse known and unknown factors, including drugs and exposure to inorganic dusts or radiation, not all exposed individuals develop fibrosis.81,82 Identifying a genetically susceptible population by genetic profiling may allow for early detection and intervention. Moreover, usual interstitial pneumonia (UIP) and acute interstitial pneumonia (AIP) have poor prognostic outcomes, whereas other types of pneumonia have relatively better prognosis and reversibility. The molecular mechanisms of such variability in the outcome of different forms of interstitial pneumonias are not yet known, and the role of genetic background in determining the outcome needs to be further explored.
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Conclusion Extensive research in the past decade has significantly improved our understanding in identifying a number of important inflammatory and fibrogenic molecules that are involved in various phases of fibrogenesis.83–87 However, the molecular and cellular interactions, transcriptional and translational regulation of the involved molecules, and their signaling events need further study. The availability of large-scale gene expression studies using microarray and proteomics may yield useful information that will not only help in determining fibrosis-specific novel genes88,89 but also help in focusing biological studies of relevant molecules. Such studies will help in designing phase-specific molecular therapeutic strategies to treat various granulomatous and fibrotic diseases.
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