Fibrosis Is It Linked to Inflammation

The primary causes of fibrosis are diverse and include toxic vapors, inorganic dusts, drugs, and radiation (4,6). Physical or chemical injuries and immunologic disorders can lead to cutaneous fibrosis such as keloids, hypertrophic scars, and scleroderma (systemic sclerosis) (4). Alcohol and viral infections are major causes of hepatic fibrosis, and glomerulonephritis, diabetic mellitus, and hypertension are major causes of renal scarring (4,6). Diffuse cardiac fibrosis is one of the major complications of hypertension usually associated with progressive heart failure (7). A number of drugs such as bleomycin, cisplatin, cyclosporine, and gentamicin can also induce fibrosis of the lung and kidney and have been instrumental in inducing fibrosis in certain experimental models (7,8).

Regardless of the cause of tissue injury, an inflammatory response immediately ensues that is followed by a complex, highly regulated, dynamic wound-healing process. However, certain types of injury can lead to a dysregulated inflammatory and wound-healing response resulting in formation of permanent scar tissue. The fibrotic process involves the replacement of functional tissue with excessive fibrous tissue in an attempt to maintain tissue integrity after repeated cycles of injury, inflammation, and repair (4,8,9). Unlike normal wound healing, no true resolution occurs in fibrosis. Instead, fibroblast proliferation and matrix synthesis persist, thereby resulting in progressive destruction of the normal parenchyma (4,6). In some cases, fibrosis ultimately results in organ failure and death. Fibrotic disease is therefore often defined as a failed wound-healing process after chronic, sustained injury (4,8-10).

Inflammatory disorders usually do not result in fibrosis, but fibrotic responses are thought to almost always be preceded by, and potentially propagated by, chronic inflammation (4,10,11). Chronic inflammation is defined as a reaction that persists for several weeks or months where inflammation, tissue destruction, and repair processes may all occur simultaneously (4,6). This form of inflammation is characterized by a large infiltrate of mononuclear cells, which includes macrophages, lymphocytes, plasma cells, and sometimes eosinophils (4,12). These cells are often recruited by chemokines generated at the site of inflammation. Furthermore, the release of specific profibrotic cytokines and chemokines can also recruit T cells that in turn can activate fibroblasts to produce collagen (4,13-15). Thus, when repeated injury occurs, chronic inflammation and repair can cause an excessive accumulation of ECM components and lead to the formation of a permanent scar, a hallmark of fibrotic disease (2,4,16,17). This process is a consequence of complex interactions among the fibroblasts, cytokines, growth factors, proteases, and ECM proteins, which function to amplify the process. However, the exact mechanism underlying the fibrotic process is not completely understood.

Recently, the notion that the chronicity of inflammation may not actually drive the fibrogenic process has been widely appreciated (Tables 1, 2, and 3). Some propose that it is indeed the alteration of the mesenchymal cell pheno-types that disrupts the balance between collagen synthesis and degradation in the wound-healing process, highlighted by clinical evidence that shows unsuccessful treatment of fibrosis with anti-inflammatory or immunosuppressive drugs (18,19). One scenario is that mesenchymal cells (myofibroblasts and fibroblasts) are phenotypically altered and thus do not undergo apoptosis after resolution.

Table 1

Hypothesis for the Pathogenesis of Fibrotic Disease

1. Chronic inflammation is a leading component and contributing event to the pathogenesis of fibrotic disease, where a normal inflammatory response to injury becomes a chronic, pathologic wound-healing response.

2. Fibrotic disease results from epithelial injury and abnormal wound repair in the absence of preceding inflammation.

3. Inflammation is a normal response to injury and, with persistent antigen or injury, results in the polarization of a profibrotic microenvironment where resident cells and inflammatory cells promote matrix deposition and not degradation.

Chemokine Receptors and Ligands in Fibrosis

Chemokine

Chemokine

receptor

ligand(s)

Cell expression

Profibrotic Antifibrotic

CCR2

CCL2/MCP-1

Macrophage, immature DC, basophil, fibroblast, T, NK, endothelial

X

CCR3

CCL11/eotaxin

Eosinophil, basophil, platelet, mast, Th2, airway epithelial

X

CCR4

CCL17/TARC

DC, basophil

CCL22

Th2, Treg, platelet

X

CKLF1

CCR5

CCL3/MIP-1a

DC, macrophage,

CCL8/MCP-2

Th1, NK

X

CCL5/RANTES

CCL7

CCR6

CCL20

Immature DC, T, B

X

CCR7

CCL21 SLC

DC, fibroblast, T, B

X

CXCR3

CXCL10/IP-10

Th1, B,

CXCL9/MIG

smooth muscle,

X

CXCL11/I-TAC

mesangial, microglia

CXCR4

CXCL12/SDF-1

DC, platelet, neutrophil, T, B, macrophage, astrocyte

X

DC, dendritic cell; NK, natural killer; Th1, T helper 1; Th2, T helper 2; Treg, T regulatory.

DC, dendritic cell; NK, natural killer; Th1, T helper 1; Th2, T helper 2; Treg, T regulatory.

Table 3

Th1 and Th2 Cytokines in Fibrosis

Table 3

Th1 and Th2 Cytokines in Fibrosis

Th1 antifibrotic

Th2 antifibrotic

IFN-y

IL-4

IL-2

IL-5

IL-12

IL-10

IL-18

IL-13

TNF-ß

CCL2/MCP-1

Increased ECM production and reduced ECM degradation persists and drives fibrotic disease. A "profibrogenic microenvironment" is maintained by the release of profibrogenic factors (TGF-P, platelet-derived growth factor (PDGF), IL-1) by the altered mesenchymal cells and resident epithelial cells (18,20). Altered structural cells and ECM are readily capable of supplying growth factors to sustain the fibrogenic process, independent of inflammatory cells (18). This dichotomy is illustrated in tendonitis ("tennis elbow"), which is now more commonly known as tendinosis. Histopathologic studies demonstrate that patients with tendinosis have small numbers of inflammatory cells in the presence of large populations of mesenchymal cells (fibroblasts and endothelial cells), in addition to increased hyperplasia, and disorganized collagen deposition (21). Interestingly, although tendinosis occurs as a result of repetitive microtrauma to the tendon, evidence of chronic inflammation is undetectable (21). Essentially, this example illustrates that the inflammation commonly observed in fibrosis possibly arises from conditions defined by the injured tissue itself and the subsequent change in the tissue microenvironment (18).

Moreover, a genetic predisposition to fibrosis is also a possible cause, further questioning the role of chronic inflammation in fibrotic disease. Profibrotic, phenotypic alterations observed in fibroblasts suggest that abnormal wound repair may occur in the absence of preceding inflammation (11,22). Overexpression of active TGF-P in lung epithelial cells causes progressive fibrosis without apparent inflammation (23). Only after fibrosis has been established (by other mechanisms) for a prolonged duration is there this accumulation of inflammatory cells (mast cells), possibly through the expression of transmembrane stem cells factor (SCF) by myofibroblasts, release of chemokines (monocyte chemoattractant protein-1 (MCP-1)/CCL2) by resident fibroblasts, or expression of IL-15 in the fibrotic tissue (24-26).

Recently, the pulmonary effects of the proinflammatory cytokine IL-1P were investigated to further delineate the relation between inflammation and fibrosis (27). In contrast with TNF-a, overexpression of IL-P caused severe acute inflammation, which was associated with tissue destruction and subsequent progressive lung fibrosis (27). The fibrotic remodeling that was observed was associated with a persistent upregulation of endogenous TGF-P, strongly suggesting that progressive fibrosis is potentially more related to an impairment of the repair process and less to chronic inflammation (27). The Smad signaling pathway is believed to be the major signaling mechanism through which active TGF-P stimulates the induction of profibrotic genes (27,28). Interestingly, Smad3-deficient mice are resistant to development of lung fibrosis but not to inflammation caused by bleomycin (27). This evidence demonstrates that IL-1P promotes pulmonary fibrosis not through the inflammatory component but rather through induction of TGF-P (27,28).

Regardless of the exact role of inflammation in the process, wound healing in fibrosis (or fibroplasia) consists of two events: recruitment and proliferation of fibroblasts at the site of injury and deposition of excessive ECM by these cells. The resulting scar tissue is observed in varying degrees in essentially every type of chronic inflammatory disease. Several cellular pathways, including immune cell activation, have been identified as the major avenues for the generation of the matrix-producing cells in diseased conditions. Although severe acute (nonrepetitive) injuries can cause substantial tissue remodeling, fibrosis that is associated with chronic (repetitive) injury is unique in that the adaptive immune response is thought to have an important role (4,14,15).

14.2.1. Cells Involved in the Fibrotic Process

Although inflammation typically precedes fibrosis, the amount of scarring is not necessarily linked with the severity of the inflammatory response, suggesting that the mechanisms that regulate fibrogenesis are distinct from those that regulate inflammation (1,4,29). Most of the fibrotic diseases have in common a persistent inflammatory stimulus and lymphocyte-monocyte interactions that sustain the production of growth factors, proteolytic enzymes, and fibrogenic cytokines and chemokines, which together promote the deposition of connective tissue elements (1,29). Fibrosis is a characteristic feature in the pathogen-esis of a wide spectrum of diseases and is a leading cause of morbidity and mortality in numerous disorders (2,4,17). Therefore, in order to develop successful treatment for fibrotic disease, it is imperative to understand the upstream mediators involved in the regulation of the fibrotic mechanism.

A relatively newly described immune cell, the fibrocyte, has been implicated in fibrotic disease, as well as in normal wound repair, granuloma formation, and antigen presentation (3,5,30-33). Evidence from patients with hypertrophic scars such as keloids, and those affected by scleroderma and other fibrosing disorders, have demonstrated fibrocytes in their lesions (3,30). Recently, a newly appreciated disease, nephrogenic fibrosing dermopathy (NFD), has been described in humans. NFD is a rare fibrotic skin condition that affects patients with renal disease, and the fibrocyte may play an important role in disease development (34,35). Initially identified as a blood-borne cell, fibrocytes also have been localized to various tissues in both normal and pathologic conditions (3,5,32,33). Morphologically, they are distinguishable from fibroblasts and leukocytes. Fibrocytes can further be characterized by their expression patterns of extracellular markers, cytokines, chemokines, and growth factors (3,5,3033). The precise origin of the fibrocyte is still unclear, and a fibrocyte-specific cell surface marker has yet to be identified (3,30). However, fibrocytes are known to express CD45, CD34, CD 11b, and/or collagen 1 and to produce matrix proteins such as vimentin, collagens I and III, and are known to participate in the remodeling response by secreting matrix metalloproteinases (MMPs) (3,5,30-33). They are a rich source of inflammatory cytokines, growth factors, and chemokines that provide important intercellular markers typical of an antigen-presenting cell (5,30,33). Moreover, fibrocytes express several chemokine receptors, such as CCR3, CCR5, CCR7, and CXCR4 (5). Secondary lymphoid tissue chemokine (SLC)/CCL21, has been reported to be a key mediator of fibrocyte trafficking, as intradermal instillation of recombinant SLC results in recruitment of fibrocytes to the injection site (5,30).

The link between fibrocytes and myofibroblasts is not clear, although some believe that fibrocytes can differentiate into myofibroblasts (19,30,33,36,37). Early evidence demonstrates that within the wound, fibrocytes differentiate in response to TGF-P and collagen and are signaled to express increased smooth muscle actin (aSMA), a marker of myofibroblasts, possibly through the IL-6 signaling (30,33,38,39). In this context, it is proposed that fibrocytes may represent a systemic source of contractile myofibroblasts that appears in many fibrotic lesions, such as those seen in chronic asthma, and various forms of pulmonary fibrosis (33,38). Indeed, they do appear to play a role in the prolif-erative phase of wound repair and because they appear early in the wound site, it is suggestive of their role in the inflammatory phase of wound healing (5).

Currently, it is widely accepted that peripheral blood fibrocytes are recruited (by chemokinetic signals) to sites of injury after fibrosis is initiated (3,5,3033,40). It is proposed that the fibrocyte is derived from the bone marrow and is recruited to the site of fibrosis, via the vasculature, only after a signal has occurred (such as in pulmonary fibrosis) (36,40). This point is strengthened by the finding that bleomycin (BLM) treatment significantly increases chemokines (CXCR4 ligand and SLC/CCL21) specific for the chemokines receptors (CXCR4 and CCR7) expressed by peripheral blood fibrocytes (36). Using a murine BLM-induced model of pulmonary fibrosis, Moore et al. demonstrated that the transition of fibrocyte to fibroblast in vitro is associated with the loss of expression of the chemokine receptor, CCR2, and expression and enhanced production of collagen 1 (40). The origin of the fibrocyte, however, and its role in mediating fibrosis is particularly controversial. Recently, using a murine model of BLM-induced pulmonary fibrosis, Hashimoto et al. reported that the collagen-expressing myofibroblasts found in the fibrotic lung appear to be derived from local, quiescent fibroblasts rather than from the bone marrow (36). These findings, which indicate a phenotypic difference between resident lung fibroblasts and those derived from bone marrow progenitor cells, challenge the theory that blood-borne fibrocytes are precursors for the myofibroblasts found in fibrotic tissue (30,33,36).

Whereas the study by Moore et al. implicates the fibrocyte as having a central, profibrotic (profibrogenic) role in the fibrotic disease, other studies suggest otherwise. Ortiz et al. show that not all bone marrow-derived cells are damaging during tissue repair (19). They demonstrate that murine mesenchymal stem cells migrate to the fibrotic lung, adopt epithelial-like phenotype, and reduce inflammation and collagen deposition in BLM-challenged mice (19). Possibly, this study can support a bone-marrow origin for fibrocytes, if they indeed are part of the milieu of cells derived from the bone marrow engraftment, while also supporting an anti-fibrotic role for fibrocytes during tissue repair (19). A recent study by Choi et al. demonstrates an increase in CCR7 expression in fibrotic lung biopsies that, interestingly, did not correlate with the presence of fibrocytes or myofibroblasts in the focal areas (37). Although the study mainly provides evidence of a pivotal role for CCR7 in idiopathic interstitial pneumonia (IIP), it also challenges the profibrotic role of the fibrocyte proposed previously. The study emphasizes that it is unlikely that the cells expressing elevated levels of CCR7 in IIP are indeed infiltrating fibrocytes or myofibro-blasts, affirming that it is the activation of resident pulmonary fibroblasts that are profibrotic (37). Notably, CCR7 has been investigated in the context of differentiation of memory T cells, dendritic cell chemotaxis during homeostatic and inflammatory conditions, and trafficking of T cells from blood to lymph nodes (41-44). Thus, identifying signals that either promote fibrogenesis or prevent an excessive wound-healing response is central in understanding fibrotic disease.

How To Reduce Acne Scarring

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