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Cardiovascular Research 1999 41(3):532-543; doi:10.1016/S0008-6363(98)00305-8
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Cardiac fibrosis and inflammation

interaction with hemodynamic and hormonal factors

Antonino Nicolettia and Jean-Baptiste Michelb,*

aINSERM U430, Broussais Hospital, 75014 Paris, France
bINSERM U460, CHU X.Bichat, 75018 Paris, France

* Corresponding author. Tel.: +33-1-4485-6160; fax: +33-1-4485-6157; e-mail: U460@bichat.inserm.fr

Received 25 May 1998; accepted 30 September 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Perivascular inflammation
 3 Proinflammatory intercellular...
 4 Proinflammatory intracellular...
 5 Peptidergic systems as...
 6 Relationship between...
 7 Specific versus unspecific...
 References
 
It is generally admitted that the pathogenesis of perivascular and interstitial cardiac fibrosis involves the response to two types of stimuli: a hormonal one, mainly involving the renin–angiotensin–aldosterone system and the more recently described endothelin system, and a hemodynamic stimulus, particularly high blood pressure. We propose in the present review a third step which, although not exclusive, interacts with the hormonal and hemodynamic ones, and involves inflammatory mechanisms. Indeed, hypertension is invariably associated with inflammatory cell infiltration either in the intimal part of large vessels or in the adventitial region of arterioles. This has led us to hypothesize that arterial wall cells may trigger the initial communications attracting inflammatory cells to the perivascular region. In this paper, we review the proinflammatory intercellular communications as well as the intracellular signaling which confer an inflammatory phenotype to arteries. In this context, the profibrogenic and proinflammatory effects of hemodynamic overload and peptidergic systems such as angiotensin II and endothelin are considered. The study of the inflammatory process is not without interest, especially in view of the strong modulating effect of the inflammatory mediators both on the inflammatory process itself and on the fibrotic process. The principal and the most potent mediators are reviewed. Finally, the hypothesis that the inflammatory process could be in reality an immune specific process is suggested.

KEYWORDS Angiotensins; Endothelin; Hemodynamic forces; Growth factors; Cytokines; Oxidative stress; Fibroblasts; Smooth muscle cells; Endothelial cells; Interstitium


   1 Introduction
Top
 Abstract
 1 Introduction
2 Perivascular inflammation
 3 Proinflammatory intercellular...
 4 Proinflammatory intracellular...
 5 Peptidergic systems as...
 6 Relationship between...
 7 Specific versus unspecific...
 References
 
Cardiac tissue is composed of cellular and extracellular compartments. The cellular compartment is mainly represented by the cardiomyocytes, responsible for the phasic contractile activity of the heart, by interstitial cells, including capillary endothelial cells, resident fibroblasts, and monocytic cells and by vascular cells from coronary arteries and veins. In between cardiomyocytes, fibroblasts synthesize the main components of the extracellular matrix: collagen I and III. Dysregulation of the synthesis and/or the degradation of the extracellular matrix can lead to severe cardiac dysfunction (and even heart failure). A typical example is provided by hypertension-related cardiac remodeling: in addition to the growth of myocytes, the interstitium also participates in the cardiac remodeling induced by pressure overload via activation and hyperplasia of fibroblasts and deposition of excess and altered types of extracellular collagen, mainly collagen I. Nevertheless, in other models of cardiac remodeling due to overload, hypertrophy of cardiac myocytes and the development of fibrosis appear to be independent phenomena. For example, physiologic cardiac hypertrophy secondary to intensive exercise, or pathological eccentric cardiac hypertrophy secondary to volume overload [1]are not associated with the development of perivascular fibrosis. Development of fibrosis appears to be an extramyocytic phenomenon associated with, but probably not due to, cardiac myocyte hypertrophy, and it is related to the response of the cardiac interstitial cellular compartment. During hypertension, the extracellular matrix expands because of reactive and reparative fibrosis [2]. Collagen I and III first accumulate around intramyocardial coronary arteries, and then the fibrosis extends to between the cardiomyocytes. This process represents the so-called reactive perivascular and interstitial fibrosis. The thickening of the extracellular matrix around cardiomyocytes is also likely to decrease their energetic supply, at the same time as the cardiac muscle workload is increased in response to systemic hypertension. This mismatch results in cell death, probably both by necrosis and apoptosis. Finally, the surrounding fibroblasts synthesize new matrix aimed at replacing the damaged cells, forming "microscars", or "scars" according to the size of the lesion. This process is called reparative fibrosis. It is noteworthy that other metabolically active tissues, such as kidneys, also develop similar interstitial fibrosis during hypertension [3].

Clearly, the understanding of the initial reactive events, i.e., the activation of perivascular and, later, of interstitial fibroblasts, is of importance. At present the triggering element is still a matter of debate. The hormones of the renin–angiotensin–aldosterone system are believed to play a major role in modulating the synthetic activity of cardiac fibroblasts [4]. But it is also clear that intracoronary pressure alone is a strong signal in directly leading to fibroblast activation. In this review, we propose a third fibrosis-triggering pathway, not independent of the hormonal control and/or blood pressure, but related to the inflammatory cells that invariably infiltrate the overloaded cardiac tissue (Fig. 1). In several fibrotic processes the role of inflammation has been clearly demonstrated. Profibrogenic cytokines are indeed released by inflammatory cells [5]. These cells also participate to the proteolytic–antiproteolytic balance controlling extracellular matrix turnover.


Figure 1
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  		Fig. 1 Putative cascade of events leading to perivascular fibrosis during cardiac overload.

 

   2 Perivascular inflammation
Top
 Abstract
 1 Introduction
 2 Perivascular inflammation
3 Proinflammatory intercellular...
 4 Proinflammatory intracellular...
 5 Peptidergic systems as...
 6 Relationship between...
 7 Specific versus unspecific...
 References
 
We have described the inflammatory process taking place in rat cardiac tissue submitted to a pressure overload. This has been shown in several models of hypertension, namely the spontaneously hypertensive rat (SHR) genetic model [6], the renovascular model [7]and the L-NAME model [8]. These data have been confirmed by the study of Haller et al. [9]showing an upregulation of c-fms gene expression, coding for the monocyte colony-stimulating factor receptor, localized on perivascular clusters of monocytes in the hypertrophied SHR heart. The L-NAME model is of great interest in the study of fibrosis and inflammation, since it evolves towards fibrosis more rapidly than other models, with end-organ damage involving the central nervous system, [10], the kidney [11]and the heart [12]. Indeed, chronic administration of L-NAME is associated with a more precocious and intensive perivascular inflammatory cell infiltration than other models of hypertension.

The increase in wall tension is distributed throughout the whole coronary arterial tree, and accordingly perivascular inflammation and fibrosis develop in both the left and right sides of the heart. Given that the fibrogenic process is specifically periarteriolar, we hypothesize that perivascular inflammation and fibrosis may be triggered partly by centrifugal communications generated by the arterial wall itself.

It has been shown that inflammatory cells [6, 9]first infiltrate the perivascular domain, where fibroblasts synthesize collagen I mRNA [6](Fig. 2) and, subsequently, infiltrate also the interstitial space. These cells have been identified as being T lymphocytes and macrophages [6, 9].


Figure 2
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  		Fig. 2 Co-localization of collagen I mRNA-expressing cells (A: in situ hybridization; B: in situ hybridization after RNAse treatment) with immunolabeled T helper (C) and T cytotoxic (F) lymphocytes, macrophages (D) and MHC class II positive cells (E) on serial tissue sections (x40) of left ventricles of renovascular hypertensive rats sacrified after 2 months of hypertension.

 

   3 Proinflammatory intercellular communications
Top
 Abstract
 1 Introduction
 2 Perivascular inflammation
 3 Proinflammatory intercellular...
4 Proinflammatory intracellular...
 5 Peptidergic systems as...
 6 Relationship between...
 7 Specific versus unspecific...
 References
 
Two cell types are specific of the vascular wall (i) endothelial cells lying at the interface between circulating plasma and blood cells with the arterial wall, and (ii) smooth muscle cells, the main cellular effector of vasomotion, and also participating in the arterial wall remodeling. Indeed, smooth muscle cells are the most solicited cells in hypertension, predominantly supporting the increase in tensional stress. On the other hand, smooth muscle cells are also the main vascular cell target of vasoactive extracellular agents responsible for secondary hypertension: angiotensin II, excess of salt and mineralocorticoids, endothelin or the absence of nitric oxide (NO). The driving agents which attract inflammatory cells to the extracellular vascular compartment have not yet been elucidated. Most probably, they consist of a mixture of different chemokines, interleukins (ILs), adhesion molecules and growth factors.

Besides their functional actions on smooth muscle cell contraction, vasoactive extracellular signals influence the phenotype of smooth muscle cells by inducing cell growth and intercellular communications via either inflammatory or endothelial cell activation. Furthermore, activated smooth muscle cells are probably able to communicate directly with fibroblasts via peptides or growth factors. Both increased mechanical stress and vasoactive agents may further modify smooth muscle cell phenotype.

Likewise, endothelial cells are functionally involved in hypertensive cardiac remodeling. Several experimental studies have shown that activated endothelial cells are involved in the migration and homing of inflammatory cells within tissues; in this way endothelial cells participate in interstitial activation. For instance, Haudenschild et al. [13]in DOCA-salt hypertensive, and Limas et al. [14]in Dahl salt-sensitive rats, have described increased interactions between inflammatory cells and endothelial cells in hypertension. These data have been extended to the SHR by Clozel et al. [15], who described the subendothelial accumulation of monocytes and macrophages, which was reversed by angiotensin converting enzyme inhibition. More recently, Kato et al. [16]and Luvarà et al. [8]confirmed these data and showed that blockade of the NO synthase activity increased further this subendothelial cell accumulation. Therefore, whatever the model, hypertension is associated with the homing of inflammatory cells in the inner, intimal part of the vessel wall in large arteries, and in the outer perivascular part in intratissue arterioles. The subendothelial accumulation of inflammatory cells possibly links hypertension and intimal atherosclerosis in humans, whereas perivascular accumulation of inflammatory cells probably links hypertension and fibrosis development in target organs such as the kidney and the heart.

The arterial wall, when submitted to high tensional stress and to vasoactive agents, produces chemokines, not yet completely catalogued, which may be involved in the centrifugal and centripetal attraction of inflammatory cells. For example, Capers et al. [17]have recently described an induction of monocyte chemoattractant protein-1 (MCP-1) expression in aortic tissue of hypertensive rats. Of interest, this study described a predominant adventitial response under chronic administration of angiotensin II or norepinephrine paralleling the increased blood pressure and expression of MCP-1 mRNA level in the aortic wall of these hypertensive animals. Pulsatile stretching of smooth muscle cells in culture (flexwell system) induces an increase in MCP-1 mRNA expression. These data suggest that upregulation of MCP-1 expression in experimental hypertension may be related to increased mechanical stress. Furthermore, growth factors such as platelet-derived growth factor (PDGF) [18]are also able to induce MCP-1 expression in cultured smooth muscle cells. The possibility of a direct effect of angiotensin II or other vasoactive agents on MCP-1 expression by vascular smooth muscle cells in culture has not yet been tested.

In our laboratory, we have described that a switch to a proinflammatory phenotype of the arterial wall, with overexpression of inducible cyclo-oxygenase type II in the media, follows chronic L-NAME administration in rats [8]. Similarly, the inducible form of NO synthase type II was overexpressed in medial smooth muscle cells in the L-NAME model. ICAM-1 and VCAM-1 were upregulated in the arteriolar endothelium and media compared with control animals in which the expression of ICAM-1 was restricted to the venous endothelium. VCAM-1 was less expressed in control animals as compared to L-NAME hypertensive animals.


   4 Proinflammatory intracellular signaling
Top
 Abstract
 1 Introduction
 2 Perivascular inflammation
 3 Proinflammatory intercellular...
 4 Proinflammatory intracellular...
5 Peptidergic systems as...
 6 Relationship between...
 7 Specific versus unspecific...
 References
 
The gene expression of these inducible isoforms of proinflammatory proteins and of VCAM-1 is reputed to be under the control of the transactivator nuclear factor kappa-B (NF{kappa}B). This has also been shown for MCP-1 [19]and for the inducible form of NO synthase [20]. In the vascular wall, the dissociation of the I{kappa}B–NF{kappa}B complex appears to be predominantly under the control of the intracellular redox balance and there is evidence showing that oxidative reactions are associated with fibrogenesis (see Ref. [21]for review) suggesting that oxidative stress could have a NF{kappa}B-dependent profibrogenic effect. Indeed, such a profibrogenic role of oxidative stress has been largely explored in the development of liver fibrosis [21]. Furthermore, many etiologic agents of fibrogenesis stimulate the production of reactive oxygen species and lipid peroxidation either directly, or indirectly through inflammatory stimuli. For instance, a moderate oxidative imbalance stimulates protein kinase C [22]and fibroblast proliferation [23]. Consistently, low amounts of lipid peroxidation end-products upregulate several enzymatic activities and display chemotactic activity [24]. In addition to their activation of NF{kappa}B, reactive oxygen species have been shown to activate the activator protein 1 (AP-1) [25]that could also explain the gene expression modulation induced by oxidant species.

Griendling and coworkers have recently described an NADPH oxidase activity in the vascular wall in vivo [26]and in smooth muscle cells in vitro [27]. As in neutrophils, NADPH oxidase cell membrane subunit p22phox participates in oxidative stress in smooth muscle cells. Smooth muscle cell activity and expression of p22phox were regulated via the phospholipase C, A2, and D signaling pathways by vasoactive peptides, such as angiotensin II [28]. Consistently, Rajagopalan et al. [29]recently demonstrated that angiotensin II-induced hypertension in rats caused an increase in vascular superoxide production. Similarly Pagano et al. [30]described a constitutively active NADPH oxidase in rabbit aortic adventitia, the activity of which was enhanced by angiotensin II. Furthermore, in a non-hypertensive model of atherosclerosis in the rabbit, converting enzyme inhibition has been reported to prevent arterial nuclear NF{kappa}B activation, monocyte chemoattractant protein-1 expression and macrophage infiltration [31]. In agreement with these results, Puri et al. [32]showed that angiotensin II-induced c-Jun/c-Fos heterodimer DNA binding was dependent upon the production of reactive oxygen intermediates within myogenic cells. All these data suggest that the "classical" protein kinase C pathway is not the only one via which angiotensin II may trigger its effects. A less well-established pathway could start from the activation of NADPH oxidase, with a consequent increase in oxidative stress, leading to activation of transcription factors such as NF{kappa}B and AP-1, thus finally inducing the expression of proinflammatory molecules such as MCP-1 or VCAM-1 (Fig. 3). To our knowledge, there are no data reporting the effect of mechanical stretch on p22phox activity in smooth muscle cells. Such an effect would constitute, as in the case of angiotensin II, a link between mechanical and oxidative stresses.


Figure 3
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  		Fig. 3 The relationship between angiotensin II, oxidative stress, inflammation and fibrosis.

 

   5 Peptidergic systems as proinflammatory and profibrogenic mediators
Top
 Abstract
 1 Introduction
 2 Perivascular inflammation
 3 Proinflammatory intercellular...
 4 Proinflammatory intracellular...
 5 Peptidergic systems as...
6 Relationship between...
 7 Specific versus unspecific...
 References
 
In parallel with the induction of chemoattractive and proinflammatory proteins within the arterial wall, vasoactive peptides such as angiotensin II, bradykinin and endothelins could play a more direct role in the induction of fibroblast and macrophage activities. As usual, the role of angiotensin converting enzyme and angiotensin II–AT1 receptor interaction has been better documented than the action of other peptidergic systems. Moreover the AT1 receptor gene transcription is under control of the protein kinase C-dependent AP-1 site, which may be activated by angiotensin II [33].

The presence of angiotensin II AT1 receptors on fibroblasts [34]and their coupling to intracellular signaling is now well-documented in animals and humans [35, 36]. Angiotensin II is a mitogen for fibroblasts from newborn rat heart [37, 38], and also increases collagen production [39]and increases endothelin and FGF-b expression in fibroblasts from adult heart [40, 41]. Thus directly or indirectly, angiotensin II is a profibrogenic agent. It has recently been proposed that trophic effects of angiotensin II on cardiac myocytes could be mediated by cardiac fibroblasts [42]and that the intercellular agent of communication could be the endothelin system [43].

The monocyte–macrophage cells also express the AT1 receptor [44, 45]. Angiotensin II activates the monocytic cells [46]and increases calcium mobilization within these cells [47]. This activity increases the adhesion of monocytic cells to endothelium [46]and the secretion of proinflammatory molecules such as tumor necrosing factor (TNF). It has been recently shown that angiotensin II was able to increase lipoxygenase activity in monocytes [48]. Therefore angiotensin II has a prooxidant effect and increases the production of lipid peroxidation end-products in monocytes.

On the other hand, inflammatory cells and particularly mast cells synthesize and secrete a serine protease of the chymase family capable of cleaving angiotensin I to produce angiotensin II [49]. Similarly, the cathepsin G of neutrophils is also capable of generating angiotensin II [50]. These angiotensin converting enzyme-independent pathways have been identified in human [51–53]baboon [54]and hamster heart [55].

Overexpression of angiotensin converting enzyme has been already reported during the development of hypertension-induced cardiac hypertrophy [56]. We [57]and others [58]have reported that this overexpression of angiotensin converting enzyme is probably not related to the hypertrophy of cardiac myocytes themselves but rather to the activation of interstitial cells, including monocyte–macrophages and activated myofibroblasts. In contrast to endothelial cells, in which angiotensin converting enzyme is constitutively expressed at a high level, expression of angiotensin converting enzyme is induced during the phenotypic evolution of the monocyte to the macrophage and of the quiescent fibroblast to the activated myofibroblast. Moreover, this inducibility of the angiotensin converting enzyme gene in non-endothelial cells is genetically modulated [59]and therefore could be one of the links between the genetically determined expression of angiotensin converting enzyme and the progression of cardiovascular disease [60]. Takemoto et al. [61]have recently reported overexpression of angiotensin converting enzyme in the periarterial areas of inflammation and fibrosis in the L-NAME model. Likewise, this group reported an upregulation of AT1 angiotensin II receptor expression in close association with the perivascular infiltration of inflammatory cells in this model [62]. Moreover, this activation seems to be dependent upon oxidative stress within the arterial wall of L-NAME administered rats. Similarly, an upregulation of bradykinin receptors has been reported to be associated with perivascular fibrosis in hypertensive animals [63]. Bradykinin facilitates fibroblast proliferation and inflammation.

Another peptidergic system, recently emerging as a profibrogenic system, is the endothelin system. Endothelin is a mitogen for fibroblasts. Endothelin antagonists are able to partially prevent hypertension-induced fibrosis in the heart and in the kidney [64]. Recently, Chatziantoniou et al. [65], using transgenic mice harboring the luciferase and β-galactosidase reporter genes under the control of procollagen I promoter showed that administration of L-NAME to these mice induced expression of the transgene. In the kidney, the expression of the transgene preceded the development of hypertension. Similar data were reported in the heart and the aorta but the procollagen expression was delayed as compared to the kidney, and was concomitant with the elevation of blood pressure. The procollagen promotor remained unstimulated in response to L-NAME in non-vascular tissues such as the tail and the skin. Interestingly, the endothelin antagonist bosentan prevented the expression of the reporter gene independently of blood pressure effects. In agreement with these results, transgenic mice overexpressing the endothelin I gene developed interstitial fibrosis independently of any evidence of hypertension [66]. Nevertheless, the origin of endothelin in hypertension remains unclear. Endothelium is usually considered to be the main source of endothelin, but endothelin expression can be also induced in smooth muscle cells in response to vasoactive peptides such as angiotensin II [63]. In vivo, overexpression of endothelin during hypertension appears to be associated with smooth muscle cell activation rather than with that of endothelial cells [67]. Therefore endothelin could be one of the intercellular signaling molecules between the vascular wall and fibroblasts.

On the other hand, NO generated by endothelial cells is probably one of the major counter-regulatory mechanisms of hypertension-induced perivascular fibrosis. For example, NO reduces expression of adhesion molecules and proinflammatory cytokines in endothelial cells [68]. This effect seems to be dependent on the redox state. The main cellular targets of vascular NO are the smooth muscle cells. By interacting with the main signaling pathway within the smooth muscle cells, NO could prevent the vascular wall remodeling, including perivascular fibrosis.


   6 Relationship between inflammatory cells and fibrosis
Top
 Abstract
 1 Introduction
 2 Perivascular inflammation
 3 Proinflammatory intercellular...
 4 Proinflammatory intracellular...
 5 Peptidergic systems as...
 6 Relationship between...
7 Specific versus unspecific...
 References
 
During the inflammation processes that take place in overloaded heart [6, 69], both macrophages and T cells may release cytokines that can act on cardiac resident cells. The metabolism and proliferation of cardiac fibroblasts and myocytes as well as the extracellular matrix turnover constitute targets for these molecules. But cytokines also amplify or inhibit by feedback the inflammatory response itself due to their chemoattractive and/or antiinflammatory properties. Among the released cytokines are ILs, TNFs, IFNs, PDGFs, FGFs, transforming growth factor (TGF)-βs... This list is obviously not exhaustive and, moreover, macrophages are also capable of synthesizing complement components, collagenases and elastases (see Ref. [70]for review). We will review a limited set of the above-cited cytokines.

6.1 TGF-βs: profibrotic, immunomodulating mediators
The TGF-β family comprises five molecules (TGF-β1 to β5) forming 25 kilodalton (kDa) dimers. These molecules are released in latent inactive forms (in the extracellular matrix, TGF-βs bind to decorin) that have to be cleaved to obtain functional molecules. Moreover TGF-β regulates expression of its own converting enzyme furin [71]. TGF-βs can be synthesized by macrophages, by B and T lymphocytes as well as by smooth muscle cells [72]and they can induce their own synthesis. TGF-βs can inhibit the colony stimulating factor-induced proliferative response of hematopoietic cells. TGF-βs have also an inhibitory effect on the proliferation of both T and B cells (see Ref. [73]for review) and decrease immunoglobulin M (IgM) and IgG secretion by activated B lymphocytes (see Ref. [74]for review). The inhibitory effect on T cells is both autocrine and paracrine [75]. Thus, TGF-βs regulate negatively the proliferative response and the differentiation of immunocompetent cells. This is illustrated by the TGF-β knockout mice, which are characterized by a massive inflammatory response in all organs, the heart and the lung being the first organs affected [76]and by the suppressing effect of TGF-β in experimental arthritis [77]. Nevertheless, some studies show that TGF-βs can also have a proinflammatory and a chemoattractive effect, especially on monocytes. They can induce the production of IL-1, PDGFs, FGFs, and TNFs by monocytes (see Ref. [78]for review). TGF-βs are also able to induce the synthesis of extracellular matrix components and they have been especially well studied in wound-healing processes (see Refs. [5, 79]for review). Moreover, TGF-βs have been reported to be involved in several fibrotic processes: (i) In the rat model of experimental glomerulonephritis, is has been shown that TGF-β1 increased synthesis of extracellular matrix components and integrins, and decreased protease activity [80–82]. This result was validated by neutralizing TGF-β1 by using antidecorin antibodies. Extracellular matrix synthesis was blocked in this way [83, 84]; (ii) In hepatic fibrosis models, TGF-βs are involved in fibrogenesis [85]; (iii) In the bleomycin-induced pulmonary fibrosis model, the TGF-β content of the lung is increased preceding the increase in collagen, fibronectin and proteoglycans [86]. In 1986, Ignotz and Massagué showed that TGF-βs stimulate the expression of fibronectin and collagens in cultured fibroblasts [87]. Later, an NF-1 site was described within the collagen I promotor region involved in the response to TGF-βs [88]. In addition, it was observed that TGF-βs induce synthesis of tissue inhibitor of metalloproteases but also of procollagenases [89].

In neonatal [90, 91]or adult heart [92, 93], TGF-βs are synthesized by cardiomyocytes and have an autocrine and/or paracrine action. Rat cardiomyocytes cultured in the presence of TGF-β express fetal genes and the re-expression of these fetal genes corresponds to the characteristic pattern of expression observed in hypertrophy induced by pressure overload [94]. In experimental infarctus models, TGF-βs are also expressed in cardiomyocytes at the edge of the infarcted area [93]and a protective role for the TGF-βs has been demonstrated during ischemic processes [95, 96]. In vivo data concerning the identification of TGF-β producing cells are still lacking: Eghbali [97]suggests that they might be heart cells other than the cardiomyocytes, the immunohistochemical staining being positive only around intramyocardial vessels in this study while Villarreal and Dillmann [34]have suggested that cardiomyocytes and/or fibroblasts may be responsible for the increased production of TGF-βs observed in hypertrophied heart related to an aortic stenosis. In our laboratory, [98], we did not find significant labeling for TGF-β1 by immunohistochemistry in left ventricles from hypertensive rats (Goldblatt model) after 4 months of hypertension, but we have detected an increase in the TGF-β1 mRNA level in the overloaded left ventricles. In vitro, cardiac fibroblasts increase their production of collagen I and III when cultured with TGF-βs [99]. Moreover, it appears that angiotensin II and TGF-βs are linked. Indeed, TGF-β1 mRNA production is greatly increased in cardiomyocytes cultured with angiotensin II via AT1 receptors [37]. Extrapolation of studies performed on vascular smooth muscle cells leads to the suggestion that the hypertrophic effect of angiotensin II may be orchestrated by its stimulation of growth factors such as TGF-βs, PDGFs and FGFs [100]. In addition to inducing the production of TGF-β1, angiotensin II activates it from its latent form [101]. In the kidney, this cooperation between angiotensin II and TGF-βs also seems to trigger the proximal tubular cell hypertrophy [102].

Schematically, it is tempting to describe TGF-βs as factors which shift the healing process from an inflammatory step that they appear to block, towards fibrosis that they stimulate. Furthermore, the TGF-βs appear to take over some hypertrophic effects from peptidergic systems in a paracrine or autocrine way.

6.2 PDGFs
PDGFs are 30 kDa proteins which were initially purified from platelet {alpha}-granules. They are composed of two subunits, A and B, forming homo- or heterodimers: AA, BB or AB. They are synthesized by a number of cells such as fibroblasts, endothelial cells, vascular smooth muscle cells and macrophages. The main effects of PDGFs are to stimulate cell proliferation and migration. They are involved in several fibrotic models [103](for review). Paradoxically, the effects of these growth factors have been little studied on cardiac or on immunocompetent cells. Nevertheless, it is known that PDGF-BB alters the profile of lymphokines produced by activated T cells [104].

PDGF-BB can induce fibroblast [38]and myocyte [105]mitosis and PDGF-AA is a potent mitogen for cardiac fibroblasts [106]. In our laboratory, we did not detect significant amounts of PDGF-A in left ventricles from normal or hypertensive rats while the PDGF-A mRNA levels were increased in left ventricles in hypertensive animals [98].

6.3 IFN and TNFs: antifibrotic agents?
Despite their extraordinary potentials, the effect of IFNs on cardiac cells are not well documented. Indeed, IFNs are pleiotropic cytokines bearing antiviral and antitumoral activities, inhibiting cell proliferation, stimulating expression of membrane antigens (receptor for immunoglobulins, MHC), and stimulating the cytotoxic function of macrophages and lymphocytes. The family is composed of four members divided into two types: type I being represented by IFN-{alpha}, -β, -{omega}, and type II by IFN-{gamma}. IFN-β is produced by fibroblasts, while the IFN-{alpha} and IFN-{omega} are produced by lymphocytes. Monocytes are also able to synthesize IFN-{alpha}. IFN-{gamma} has been shown to decrease the synthesis of extracellular matrix [107, 108]and to increase metalloproteinase synthesis in human fibroblasts [109].

The TNF family includes two members: TNF-{alpha} and TNF-β (the latter previously named lymphotoxin). TNF-{alpha} is produced by a number of cells including inflammatory cells, fibroblasts, smooth muscle cells and endothelial cells. This factor is considered to be proinflammatory and can induce the expression of several mediators such as IL-1, IL-6, MCP-1, PDGF, TGF-β, and NO synthase, among others. In fibroblasts, TNFs can induce the production of collagenases and decrease the production of collagens and fibronectin. TNFs can induce NO production and the expression of class I MHC molecules which, in turn, increase the permeability of endothelial cells.

It is known that failing human heart expresses TNF and its overexpression leads to congestive heart failure in TNF transgenic mice [110, 111]. Moreover, adult mammalian myocardium elaborates biologically-active TNF in response to hemodynamic pressure overloading [112]. This TNF could provoke a hypertrophic growth response in cardiac myocytes as shown with cultured feline cardiomyocytes [113]and could also induce the infiltration of immune cells into the myocardium during hypertension since TNF is a potent immune system stimulator. Furthermore, TNFs can induce apoptosis of cardiomyocytes (see Ref. [114]for review). This is probably why antiTNF antibodies improve myocardial recovery after ischemia and reperfusion [115].

6.4 ILs: playing on both sides
IL-1 presents the distinctive feature compared to the other cytokines, of being stored within the cells. Inflammatory cells and fibroblasts have the capacity to produce IL-1 upon stimulation. There are various inducing signals for its production including IFNs, TNFs, IL-2, complement components, class I MHC and IL-1 itself. IL-1 can modulate specific as well as non-specific immune responses and can induce (in the case of fibroblasts and vascular smooth muscle cells via PDGFs) or inhibit (in the case of endothelial cells) cell division. In various fibrotic processes such as systemic sclerodermia or pulmonary fibrosis, IL-1 is oversynthesized (see Ref. [116]for review).

IL-6, a glycoprotein of 26 kDa, is secreted by a large panel of activated cells such as macrophages, T and B lymphocytes, natural killers, fibroblasts, endothelial cells, and vascular smooth muscle cells. IL-6 release is often driven by other cytokines such as IL-1 or TNFs. IL-6 can act on very different cell types. For instance, IL-6 increases the immunoglobulin synthesis of activated B cells bearing the IL-6 receptor. IL-6 can activate fibroblasts, and induces vascular smooth muscle cell hypertrophy. IL-6 stimulates PDGF synthesis in vascular smooth muscle cells [117]and their proliferation [118]which in turn produce IL-6 [119]. In macrophages, IL-6 synthesis is blocked by TGF-βs, IL-4 and IL-10 (Th2 cytokines). IL-6 plasma levels are increased during infections, myocardial infarction and surgery (see Ref. [116]for review). Recently, elevated circulating levels of TNF and IL-6 have been correlated in severe heart failure [120].

Knowledge of the effects of the other ILs on cardiac cells is still incomplete. For instance, IL-2 is known to be cardiotoxic and its cardiotoxicity is due to lymphocyte activation [121]. We also know that IL-8 is transiently increased in the early phase of human myocardial infarction [122].


   7 Specific versus unspecific interstitial inflammation
Top
 Abstract
 1 Introduction
 2 Perivascular inflammation
 3 Proinflammatory intercellular...
 4 Proinflammatory intracellular...
 5 Peptidergic systems as...
 6 Relationship between...
 7 Specific versus unspecific...
References
 
As proposed in atherosclerosis, an exciting hypothesis to consider in the context of cardiac fibrosis is that the inflammatory cells infiltrating the cardiac tissue are specific for an antigen or a limited set of antigens. Supporting this idea, numerous CD4 T helper cells are found around the coronary artery, the site where inflammatory cells are first observed. Furthermore, the macrophages, which are antigen-presenting cells, express high levels of MHC class II molecules in the perivascular area. These molecules are expressed when an antigen is processed. A peptide within the antigen sequence is selected and a complex MHC class II/peptide is presented at the surface of the antigen-presenting cell. This complex will then be possibly recognized by a T cell clone. After recognition, the clone will proliferate and will produce cytokines, among which some could have potent effects on fibrogenesis. This line of research is exciting because the characterization of the target of this putative specific T cell response could lead to strategies aimed at preventing these immune events. This will provide a clue to the exact role of these inflammatory cells, i.e., whether they are protective or harmful.

7.1 Relationship fibrosis–inflammation: a story made of words
Finally, the theoretical basis of this model is not new and has been extensively addressed in organs... The question remains which intercellular communications and intracellular signaling pathways are specific to fibrosis development in the cardiovascular system.

The relationship between fibrosis, inflammation, the vascular wall and cardiac hypertrophy may be considered as analogous to using a language with words; the words being hemodynamic stress, the redox state, peptides and cytokines (Fig. 4). There are specific intercellular communications as well as specific intracellular signaling pathways. Clearly, inflammatory cells have the potential to strongly regulate the behavior of resident cells. It is also apparent that resident cells are not mute: they also talk to the inflammatory cells and it is likely that they send the initial message to attract the inflammatory cells to the heart in response to hemodynamic stress, hormones and peptides. Understanding the relationship between inflammatory cells and resident cardiac cells is essential because the balance of the cross-talk between these cells leads to either fibrosis or recovery [123].


Figure 4
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  		Fig. 4 The main cytokines influencing fibrosis and inflammation and the potential producing cells. Arrows symbolize positive effects while lines ending by a minus sign indicate negative effects.

 
Time for primary review 31 days.


   References
Top
 Abstract
 1 Introduction
 2 Perivascular inflammation
 3 Proinflammatory intercellular...
 4 Proinflammatory intracellular...
 5 Peptidergic systems as...
 6 Relationship between...
 7 Specific versus unspecific...
 References
 

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