Abstract
Acute aortic dissection (AAD) is a life-threatening disease with an incidence of about 2.6–3.6 cases per 100,000/year. Depending on the site of rupture, AAD is classified as Stanford-A when the ascending aortic thoracic tract and/or the arch are involved, and Stanford-B when the descending thoracic aorta and/or aortic abdominal tract are targeted. It was recently shown that inflammatory pathways underlie aortic rupture in both type A and type B Stanford AAD. An immune infiltrate has been found within the middle and outer tunics of dissected aortic specimens. It has also been observed that the recall and activation of macrophages inside the middle tunic are key events in the early phases of AAD. Macrophages are able to release metalloproteinases (MMPs) and pro-inflammatory cytokines which, in turn, give rise to matrix degradation and neoangiogenesis. An imbalance between the production of MMPs and MMP tissue inhibitors is pivotal in the extracellular matrix degradation underlying aortic wall remodelling in dissections occurring both in inherited conditions and in atherosclerosis. Among MMPs, MMP-12 is considered a specific marker of aortic wall disease, whatever the genetic predisposition may be. The aim of this review is, therefore, to take a close look at the immune-inflammatory mechanisms underlying Stanford-A AAD.
In recent years the identification of inflammatory mechanisms potentially underlying Stanford-A AAD has been a challenge; the aim of this review is therefore to point out the inflammatory/matrix degrading pathways involved in aortic rupture related both to inherited connective tissue diseases and to atherosclerosis.
Introduction
Acute aortic dissection (AAD) is a life-threatening disease with an incidence of about 2.6–3.6 cases per 100,000 per annum (Citation1). AAD is characterized by medial degeneration with tearing of the intima layer and the crossing of blood into the artery wall, which causes the formation of a false lumen within the middle tunic. Inherited tissue connective diseases (ITCD) and atherosclerosis (ATS) are the main diseases related to AAD, but trauma, certain types of vasculitis, and infections are also common causes of aortic breakage (Citation2). Depending on the site of rupture, AAD is classified as Stanford-A type when the ascending aortic thoracic tract and/or the arch are involved, and Stanford-B when the descending thoracic aorta and/or aortic abdominal tract are targeted (Citation2). Stanford-A is the most frequent type of dissection, and it occurs in almost 75% of all cases with a mortality reaching 90% if untreated (Citation3,Citation4).
It was generally believed that different diseases were responsible for dissections occurring in the different aortic tracts. In particular, Stanford-A AAD has been mostly associated with ITCD (Citation1), and Stanford-B with ATS. It is well known, however, that most ascending dissections occur in hypertensive men, with no genetic predisposition, in the sixth decade of life (Citation2,Citation4). Peak incidence of this disease, indeed, is bimodal: one peak is before patients are 40 years old, and it is mainly related to inherited diseases; the other one involves people in their 60s or older, and has been mostly associated with ATS (Citation2).
The main histological finding described in aortic diseases related to arterial wall weakening, such as aneurysm/dissection, is medial degeneration, which consists of a profound degradation of the extracellular matrix (ECM) related to smooth muscle cell (SMC) depletion, elastic fibre fragmentation, and collagen degradation (Citation5,Citation6). In such a context, an imbalance between the production of metalloproteases (MMPs; enzymes for degrading the ECM) and their tissue inhibitors (TIMPs) has been shown to play a central role in the destructive process leading to AAD. This is the case at any aortic site, both in inherited diseases and in ATS (Citation7–12). It was recently shown that immune-inflammatory mechanisms contribute greatly to aortic wall remodelling, whatever the genetic predisposition may be (Citation13–16); this suggests that inflammation and matrix degradation are common steps in the complex process leading to Stanford-A AAD, whether it is related to ITCD or to ATS.
In recent years the identification of pathogenic pathways underlying Stanford-A AAD has been a challenge, and the authors wish to review current knowledge about immune-inflammatory mechanisms involved in this disease.
Molecular and cellular players underlying Stanford-A AAD
Arterial wall remodelling depends upon a complex interaction between cells, pro-inflammatory mediators, and MMPs, regulated by an immune response. A predominant T helper 1-lymphocyte response has been associated with the proliferative pattern leading to plaque formation (Citation17,Citation18), whereas T helper 2-lymphocytes have been related to the development of atherosclerotic abdominal aneurysm (Citation7,Citation19). Macrophages and their related products have been suggested as playing a fundamental role in triggering and maintaining the intraparietal inflammatory/matrix degrading processes underlying ascending thoracic aortic dissection, both in patients with ITCD and in those with no genetic predisposition (Citation14–16,Citation20,Citation21). Saraff et al. have shown that in mice apoE-/E- continuous infusion of angiotensin II (AGII) leads to the early recall of medial macrophages, which occurs at 1–4 days after infusion and is accompanied by elastin fibre disruption. A continuation of infusion causes three different possible effects: 1) dissection, which occurs by 1–10 days after infusion; 2) aneurysm development, which arises by 14 days; and 3) plaque formation, which appears 28 days after infusion. Interestingly T and B lymphocytes were detectable only inside aortic specimens collected from aneurysms and plaque (Citation20). Taken together, these observations firmly support the hypothesis that innate immunity is mainly related to the destructive pattern underlying aortic wall rupture; acquired immunity, however, is mostly involved in managing plaque development, which needs a longer time.
Inherited connective tissue diseases
ITCDs related to Stanford-A AAD mainly include Marfan syndrome (MFS), family thoracic aortic aneurysm syndrome (FTAAS), and bicuspid aortic valve (BAV) (Citation1). It has been shown that mutation of the fibrillin-1 gene, which is the most common mutation expressed by Marfan patients, leads to greater production of transforming growth factor (TGF)-β and greater activity by angiotensin II (AGII) and MMPs, especially MMP-2, -9, -11, -14, -19, and -3, which results in ECM degradation (Citation21,Citation22). Matrix-degraded products, in turn, are able to amplify inflammation by inducing macrophage recruitment and their activation within the aortic wall (Citation23). AGII also contributes to maintaining an inflammatory/destructive environment by promoting the release of interleukin (IL)-6, tumour necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, vascular endothelial growth factor (VEGF), and MMPs (Citation24–26). Currently, an immune inflammatory infiltrate made up of macrophages and T and B lymphocytes has been found within the middle and outside tunics of dissected aortic specimens collected from patients affected by MFS and FTAAS (Citation21). It is interesting to note that vasa vasorum displayed an activated endothelium, suggesting that immune cell recruitment occurs through the outer tunic (Citation21). Similarly, it has been shown that in congenital BAV, shear stress leads to inflammatory cell recruitment, VEGF release and endothelial cell apoptosis, resulting in valve inflammation, remodelling, and calcification. It has also been observed that BAV valve damage is related to the presence of M1 macrophages within the cusps (Citation27). The link occurring between shear stress and M1 macrophages seems to be of particular interest. M1, indeed, is a high pro-inflammatory macrophage subset, which is able to produce TNF-α, IL-1, IL-6, and IL-12. It has therefore been suggested that the same inflammatory pathways underlie Stanford-A AAD in patients with BAV (Citation27).
Among pro-inflammatory cytokines, IL-6 and IL-8 seem to be specifically involved in promoting ascending thoracic aorta dissection in both ITCD and ATS (Citation16,Citation22,Citation28). In particular, an increase of IL-2, IL-6, IL-8, and TGF-β gene expression has been found in patients affected by Stanford-A AAD. Moreover, a significant rise in IL-6 levels has been reported both in humans affected by FTAAS and in mice genetically predisposed to ascending thoracic aorta aneurysm/dissection (Citation21,Citation29). Furthermore, Ju et al. have shown that IL-6-mediated inflammatory signalling is activated in the medial layer of aneurysms occurring in the ascending aorta of fibrillin-deficient mice, which represents a murine model for MFS (Citation30). This suggests that IL-6 is profoundly involved in inflammatory pathways underlying rupture of the aortic wall in inherited diseases.
Atherosclerosis
Although ITCD and ATS are two different conditions related to Stanford-A AAD, it is plausible that aortic rupture depends upon the activation of some common inflammatory pathways shared by these two diseases. In the same way as described for patients affected by ITCD, and in aortic specimens collected from Stanford-A AAD patients with no genetic predisposition, the presence of an immune-inflammatory infiltrate made up of activated macrophages and T and B lymphocytes has been seen in middle and outside tunics (Citation13–16). It should be pointed out that several studies have confirmed, both in mouse apoE-/E- and in humans, that macrophage recruitment and their activation inside the middle tunic are key events in the early phases of Stanford-A AAD (Citation16,Citation20,Citation25). Macrophages, indeed, are able to release and regulate the activity of several pro-inflammatory cytokines and MMPs, which in turn play a crucial role in maintaining intraparietal inflammation which leads to matrix degradation (Citation16). The authors have previously described, using molecular and immuno-histochemical techniques, how macrophages were the main cellular population infiltrating the middle tunic aortic specimens collected from patients with Stanford-A AAD with no genetic predisposition, whereas T CD4+ lymphocyte subpopulations were significantly lower, both in aortic samples and in peripheral blood. The authors’ results also showed that serum levels of T helper 1 cytokines were significantly lower than macrophage products (Citation15). Several researchers have observed that some macrophage cytokines and MMPs, such as IL-6, IL-8, and MMP-12, are greatly involved in the development of abdominal aortic aneurysms (AAAs) (Citation28,Citation31) and Stanford-A AAD (Citation16,Citation32). It has therefore been suggested that these two cytokines can be useful in making an early distinction between aortic aneurysm/dissection and athero-occlusive lesions (Citation28). Nevertheless, the wide expression of such cytokines in several inflammatory diseases makes it difficult to identify any specific pathogenic relationship of theirs with aortic wall diseases (Citation32).
Metalloproteinases
MMPs include a wide spectrum of zinc-dependent collagenases and elastases, which belong to the superfamily of metzincins (Citation33), and they are involved in the breakdown of ECM. Each MMP is differently expressed in tissues and during inflammation, thus exerting specific functions (Citation34). These enzymes are produced and secreted by several immune and matrix-resident cells of the vascular wall. TIMPs are the most specific endogenous inhibitors of MMPs (Citation34). A co-ordinated action by MMPs and TIMPs is needed for physiological ECM remodelling, whereas the imbalance between the production of MMPs and TIMPs leads to excessive ECM degradation (Citation8,Citation9,Citation34,Citation35). Although the degradation of ECM is their main function, MMPs also exert pleiotropic roles by acting on non-matrix substrates (Citation36,Citation37). It has even been shown that proteolysis mediated by MMPs regulates the transmigration of inflammatory cells from vessels to target tissues and modulates the availability of several bioactive non-matrix molecules such as growth factors, cytokines, chemokines, complement factors, cell surface protein, and apoptotic products, thus regulating immune and inflammatory responses (Citation38,Citation39). It has been seen that by their own activity MMPs play a central role in the tissue remodelling underlying several systemic and local inflammatory diseases such as asthma, multiple sclerosis, cancer, arthritis, skin and bowel diseases, and ATS (Citation10,Citation37,Citation39–42). MMPs, indeed, facilitate leukocyte recruitment, favour vascular smooth muscle cell (VSMC) migration into the intimal space, and promote neoangiogenesis. Moreover, MMPs also display defensive and anti-inflammatory functions (Citation43,Citation44). It has been shown that these enzymes, via their degrading properties, are able to process and inactivate several molecules involved in inflammation and leukocyte recruitment such as MCP-3, TNF-α, Fas ligand, and stromal cell-derived factor-1α and -1β, thus exerting anti-inflammatory functions (Citation44). In particular, it has been reported that MMP-3, -8, -13, and MT1-MMP are able to inhibit leukocyte recruitment in several models of systemic inflammatory diseases such as arthritis and lung injury (Citation39). It has also been observed that MMP-12 exerts direct antimicrobial activity and plays a role in the macrophage-mediated killing of Gram-negative and Gram-positive bacteria (Citation45).
Considering their complex functions, blocking MMP activity may represent a crucial step in preventing the progression of tissue damage in several diseases (Citation46). Currently, inhibiting MMP-12 has been shown to reduce the extent of aneurysm and rate formation in atherosclerosis-prone mice (Citation31).
In this context, it has been proposed that localized chronic inflammation, such as occurs in periodontitis, leads to a systemic release of pro-inflammatory cytokines and MMPs. These, in turn, can promote the establishment of a pro-atherogenetic state (Citation46–48). Recent studies have suggested that there is a link between cardiovascular risk and oral infection. Virulent periodontal pathogens, indeed, have been shown to promote a systemic release of IL-1, IL-6, and TGF-β and to induce foam cell formation in vitro. It has therefore been suggested that treating local inflammation can lower cardiovascular risk (Citation46,Citation47). Tetracyclines have been shown to be useful in treating several localized inflammatory oral and cutaneous diseases, but also in preventing aortic aneurism/dissection by lowering the local and systemic release of MMP-2, -9, IL-6, TNF-α, MCP-1, and C-reactive protein (CRP) (Citation46–48).
ADAMs/ADAMTSs
The metzincin superfamily, in addition to MMPs, includes ADAMs (a disintegrin and metalloproteases) and ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) (Citation33). ADAMs are, with only a few exceptions, multi-domain transmembrane proteins. ADAMs can activate a variety of chemokines, cytokines, and growth factors, which are expressed as proforms on the cell surface, thus regulating autocrine and paracrine signalling pathways. As a consequence, ADAM proteins are involved in fertilization and development, but also contribute to the progression of several diseases including atherosclerosis, Alzheimer's disease, and cancer (Citation49). ADAMTSs are soluble molecules involved in ECM turnover. In the same way as ADAMs, they have been involved in organogenesis and fertility, but also in inflammation, arthritis, and cancer (Citation50). Similar to MMPs, ADAMs and ADAMTSs have been implicated in vascular diseases. In particular, ADAMTS-1 and ADAMTS-4 were found to be highly expressed in macrophage-rich areas of human atherosclerotic plaque (Citation51,Citation52). It has also been observed that ADAMTS-1 expression was significantly up-regulated in patients with thoracic aortic aneurism (Citation52–54). Recently, Ren et al. have shown that ADAMTS-1 and ADAMTS-4 were expressed in medial VSMCs and macrophages in patients with Stanford-A AAD and no genetic predisposition, suggesting a pathogenic role for this enzyme in aortic wall remodelling (Citation54). It has also been suggested that ADAM-8 and -15 can distinguish between patients with ascending aorta aneurisms and those at higher risk of dissection. B-lymphocyte infiltrate and ADAM-8 and -15 expression within aortic wall seem to be suggestive of active parietal remodelling (Citation55).
Metalloproteinases and Stanford A-AAD in inherited connective tissue diseases
The imbalance between MMPs and TIMPs underlies aortic rupture occurring at any age and at any aortic site, both in patients with ITCD and in those with ATS (Citation8,Citation10). In particular, MMP-1, -2, -9, and -12 serum levels and tissue expression have been shown to be higher in Stanford-A AAD, whether or not there is genetic predisposition (Citation10,Citation11,Citation41,Citation56–59). Weis-Muller et al. have also reported that genes encoding for MMP-11, -14, and -19 were over-expressed in dissected ascending thoracic aortic specimens collected from patients of any age, whereas genes that encode for ECM components were down-regulated (Citation22).
It is interesting to note that different patterns of MMPs/TIMPs specifically characterize Stanford-A AAD associated with different inherited diseases. In particular, increased MMP-12, MT1-MMP, and TIMP-2 levels and a reduction of MMP-2 and TIMP-3 values distinguish patients with MFS (Citation10). In these patients it has been reported that increased levels of MMP-3 are related to a risk of dissection (Citation60).
In BAV an increase of MMP-1, -2, -9, and -12 tissue expression and a reduction of MMP-7, -8, TIMP-1, and -4 activity have been shown. In this disease, increased MMP-2 and -9 levels and decreased TIMP-1 and -2 values have been related to Stanford-A AAD. It has been suggested that MMP-2 plays a specific role in the early identification of patients at a higher risk of dissection (Citation56). Taking these observations together suggests that genetic predisposition can electively affect some MMP/TIMP pathways.
In this context, a particular annotation regards MMP-12, which has been specifically related to ascending thoracic aortic aneurysms/dissections occurring in MFS and BAV (Citation41). However, it has recently been shown that MMP-12 can be considered a specific marker for aortic wall diseases, whatever the genetic predisposition (Citation16,Citation32,Citation61,Citation62).
Metalloproteinases and Stanford A-AAD in atherosclerosis
A widespread release of MMPs, such as MMP-1, -2, -3, -8, -9, and -12, and a reduction of TIMP-1 and -2 have been reported in patients with aortic wall diseases and no genetic predisposition. Unlike inherited conditions, to our knowledge no specific distinguishing MMP/TIMP pattern has been identified in Stanford-A AAD related to ATS (Citation63–66). Due to their own pleiotropic functions MMPs are generically related to ATS, whatever its occlusive or rupture features (Citation16,Citation63,Citation67). In this field, MMP-2 and -9 have been studied intensively. In particular, it has been shown that levels of these two enzymes were significantly higher in patients with Stanford-A AAD, but also in patients with carotid and coronary ATS (Citation59). In the same way, higher levels of MMP-1, -3, and -8 have been observed in Stanford-A AAD (Citation58,Citation65), but, despite higher levels of MMP-3 in AAD patients when compared with healthy subjects, its levels were significantly lower when compared with those of patients affected by acute myocardial ischemia. This suggests that MMP-3 is mainly related to coronary artery stenosis (Citation59).
MMP-12, though, seems to be specifically related to aortic wall diseases. MMP-12 belongs to the subgroup of elastases and, unlike the other MMPs, is exclusively secreted by macrophages, so that it is also known as ‘macrophage elastase’. MMP-12, in addition to elastin, degrades a broad spectrum of substrates including type IV collagen, fibronectin, laminin, vitronectin, proteoglycans, chondroitin sulphate, myelin basic protein, δ-1-antitrypsin, and plasminogen (Citation68,Citation69). This enzyme is also able to activate MMP-2 and MMP-3, which then leads to the activation of MMP-7, -8, and -13. This auto-amplifying cascade induces a wider degradation of ECM proteins (Citation69). Several studies have confirmed that MMP-12 is involved in the progression of aortic wall damage. In particular, MMP-12 has been shown to play a pivotal role in the matrix degradation underlying abdominal aneurism development, in both humans and mice prone to ATS (Citation16,Citation31,Citation32,Citation61,Citation62,Citation70). In this way, an attenuation in the rate and the extent of experimental aneurysm formation has been shown in mice without MMP-12 (Citation31). In line with this, an increase of this enzyme has been observed in both the peripheral blood and in aortic specimens of Stanford-A AAD patients with no genetic predisposition (Citation8,Citation27), but also in patients with MFS and BAV (Citation41). This strongly suggests that MMP-12 plays a specific role in identifying patients with greater risk of aortic aneurysm/dissection, whatever their genetic predisposition. Moreover, this specific relationship between MMP-12 and Stanford-A AAD strongly supports the hypothesis of a major role of macrophages in aortic wall weakening.
Arterial hypertension
It is common knowledge that arterial hypertension (AH) is a main risk factor associated with AAD in both patients with inherited diseases and those with no genetic predisposition. It is well known that AH affects the arterial wall directly and indirectly by acting as a pro-inflammatory trigger (Citation71,Citation72). In particular, it has been shown that parietal stress can induce intraparietal macrophage recruitment and activation. Hypertensive patients display increased serum levels of IL-6, IL-8, MCP-1, VEGF, and MMP-2 and -9 (Citation73,Citation74), strongly suggesting that AH is able to promote a pro-inflammatory state which leads to excessive matrix degradation and culminates in aortic wall rupture. Blocking AGII has been shown to reduce pro-inflammatory cytokine levels and the extent of AAAs in mice prone to ATS (Citation75,Citation76).
Conclusions
Stanford-A AAD is the result of deep remodelling of the aortic wall structure related to different pathological conditions, ranging from ITCD to ATS. Macrophage recruitment and their activation within the aortic wall play a crucial role in triggering and maintaining the inflammatory/matrix-degrading process underlying Stanford-A AAD. Pro-inflammatory cytokines and MMPs are the main players involved in this process. It has been shown in both humans and mice that some macrophage products such as IL-6, IL-8, and MMP-12 are specifically related to aortic wall weakening, independently of genetic predisposition. This confirms that Stanford-A AAD is characterized by a peculiar pattern of immune-inflammatory response, which arises both in ITCD and in ATS.
MMPs and TIMPs play a central role in Stanford-A AAD. They are responsible for ECM degradation and actively participate in maintaining inflammation throughout their effects on non- matrix bioactive substrates. Interestingly, some specific MMP/TIMP patterns seem to characterize dissections occurring in different ITCDs, whereas in Stanford-A AAD related to ATS a wide over-expression of MMPs has been described.
Unlike other MMPs, MMP-12 seems to be specifically associated with Stanford-A AAD occurring both in ITCD and ATS, so that this MMP seems to be uniquely useful in the early distinguishing of patients with dissection from those with athero-occlusion.
Table I. MMP behaviour in Stanford-A AAD related to ITCD and ATS.
Funding: No funding has been received.
Declaration of interest: The authors have no conflict of interest to declare, including specific financial interest or any relationship with pharmaceutical companies, biomedical device manufacturers, or other corporation whose products or services are related to the subject matter of the article. Such relationships include employment by and industrial concern, ownership of stock, membership of a standing advisory council or committee, being on the board of directors or being publicly associated with a company or its products. Moreover the authors declare that they have not received honoraria, fees, grants, or funds from such corporations or individuals representing such corporations.
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