elastin and Aortitis

Studies of autoimmune diseases have not yet elucidated why certain organs or vessels become the objects of injury while others are spared. This paper explores the hypothesis that important differences exist in regions of the aorta; these regional variations determine vulnerability to such diseases as atherosclerosis, aortitis, giant-cell arteritis, and Takayasu's disease. The reader is invited to reassess two issues: (1) whether the aorta is indeed a single homogeneous structure; and (2) whether the initial stage of aortitis (and indeed other diseases considered "autoimmune") may primarily be the result of acquired alterations of substrate that influence unique immune profiles, but that by themselves may not be pathogenic. Disease susceptibility and patterns are influenced by many factors that are either inborn or acquired. Examples include genetic background, gender, ethnicity, aging, prior and concomitant illnesses, habits, diet, and exposure to toxins and other environmental hazards. Studies of vascular diseases must assess how such variables affect regional anatomic differences in endothelial cells, subendothelial matrix, and vascular smooth muscle, as well as the response of each to a variety of stimuli.

Topics: Aging; Animals; Aortitis; Atherosclerosis; Collagen; Disease Models, Animal; Elastin; Giant Cell Arteritis; Humans; Immune System; Takayasu Arteritis; Vasculitis

To date, aneurysm research has been primarily descriptive, reiterating the complex nature of the disease process. Enhanced by the convergence of matrix biochemistry, cell biology and immunology, this work is providing important new insight into how matrix metabolism is regulated in the diseased aorta. The focus is now on the inflammatory process and its regulation of the matrix remodeling which occurs with abdominal aortic aneurysm. A family of matrix-degrading enzymes appear to have a central role in this process. As we have learned from the evolution of the treatment of other pathologic processes such as peptic ulcer disease, the most effective pharmacologic therapies are designed from a thorough understanding of the pathophysiology of the disease. We are quickly moving forward in formulating a comprehensive understanding of the various complex interactions that result in the formation of aortic aneurysm. Given the progress of the past decade, we can expect the identification of aneurysm-associated genes and clinical trials of anti-inflammatory medications and protease inhibitors as we enter the 21st century.

Topics: Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortitis; Collagen; Elastin; Extracellular Matrix; Humans; Metalloendopeptidases; Muscle, Smooth, Vascular

Past concepts of aneurysmal dilatation as a passive process of attenuation are oversimplified and inaccurate. Aneurysm formation is a complex remodeling process that involves both synthesis and degradation of matrix proteins. Interstitial procollagen gene expression is increased in AAA compared to AOD or normal aorta, whereas tropoelastin gene expression is decreased in both AOD and AAA. The medial elastin network is disrupted and discontinuous in small AAA. Thus, the growth rate of an established AAA may well relate to the balance between collagen synthesis and degradation. Although the increased procollagen expression found in AAA may represent a compensatory response, understanding the factors that modulate matrix metabolism in AAA may allow for development of pharmacologic strategies which effectively inhibit the growth of small aneurysms.

Topics: Animals; Aorta; Aortic Aneurysm, Abdominal; Aortitis; Arteriosclerosis; Cattle; Collagen; Elastin; Extracellular Matrix Proteins; Humans; Platelet-Derived Growth Factor; RNA, Messenger; Tensile Strength

We now know our past concepts of AAA pathogenesis to be oversimplified and inaccurate. In fact, the metabolic activity of the aneurysm wall is markedly increased in comparison with normal aorta. It has become clear that AAAs result not from passive dilatation, but from a complex remodeling process involving both the synthesis and degradation of matrix proteins. Our understanding of this process has been advanced by applying molecular biology techniques. Although elastin fragmentation and medial attenuation remain the most striking histological features of AAA tissue, experimental and clinical evidence suggests that the adventitia, which is predominantly collagen, is capable of maintaining the dimensional stability of the aorta in the absence of the medial elastin network. Thus, although factors that result in fragmentation and attenuation of elastin may be important in the etiology of AAA, factors regulating the balance of collagen synthesis and degradation likely determine the rate of AAA progression. The resident inflammatory cells in AAA undoubtedly play an important pathological role in aortic dilatation. Thus, understanding the interaction between aortic mesenchymal cells (smooth muscle cells and fibroblasts) and inflammatory cells (lymphocytes and macrophages) should allow for the identification of genetic factors that predispose to AAA. In addition to the possibility of early identification of patients at risk for AAA, new insights into AAA pathogenesis might allow for development of pharmacological strategies for inhibiting expansion of small AAA.

Topics: Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortitis; Arteriosclerosis; Collagen; Elastin; Endopeptidases; Extracellular Matrix Proteins; Humans

Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell-wall extract (LCWE)-induced KD vasculitis mouse model.. We discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KD mouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KD mice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r(-/-), Il1a(-/-), and Il1b(-/-) mice were protected from KD associated AAA. Infiltrating CD11c(+) macrophages produced active caspase-1, and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with interleukin (IL)-1R antagonist (Anakinra), anti-IL-1α, or anti-IL-1β mAb blocked LCWE-induced AAA formation.. Similar to clinical KD, the LCWE-induced KD vasculitis mouse model can also be accompanied by AAA formation. Both IL-1α and IL-1β play a key role, and use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortitis; Caspase 1; Cell Proliferation; Cell Wall; Dilatation, Pathologic; Disease Models, Animal; Elastin; Female; Gene Expression Profiling; Genotype; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Interleukin-1beta; Lacticaseibacillus casei; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout; Mucocutaneous Lymph Node Syndrome; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NLR Family, Pyrin Domain-Containing 3 Protein; Phenotype; Receptors, Interleukin-1 Type I; Signal Transduction; Time Factors

Thrombomodulin (TM), a glycoprotein constitutively expressed in the endothelium, is well known for its anticoagulant and anti-inflammatory properties. Paradoxically, we recently found that monocytic membrane-bound TM (ie, endogenous TM expression in monocytes) triggers lipopolysaccharide- and gram-negative bacteria-induced inflammatory responses. However, the significance of membrane-bound TM in chronic sterile vascular inflammation and the development of abdominal aortic aneurysm (AAA) remains undetermined.. Implicating a potential role for membrane-bound TM in AAA, we found that TM signals were predominantly localized to macrophages and vascular smooth muscle cells in human aneurysm specimens. Characterization of the CaCl2-induced AAA in mice revealed that during aneurysm development, TM expression was mainly localized in infiltrating macrophages and vascular smooth muscle cells. To investigate the function of membrane-bound TM in vivo, transgenic mice with myeloid- (LysMcre/TM(flox/flox)) and vascular smooth muscle cell-specific (SM22-cre(tg)/TM(flox/flox)) TM ablation and their respective wild-type controls (TM(flox/flox) and SM22-cre(tg)/TM(+/+)) were generated. In the mouse CaCl2-induced AAA model, deficiency of myeloid TM, but not vascular smooth muscle cell TM, inhibited macrophage accumulation, attenuated proinflammatory cytokine and matrix metalloproteinase-9 production, and finally mitigated elastin destruction and aortic dilatation. In vitro TM-deficient monocytes/macrophages, versus TM wild-type counterparts, exhibited attenuation of proinflammatory mediator expression, adhesion to endothelial cells, and generation of reactive oxygen species. Consistently, myeloid TM-deficient hyperlipidemic mice (ApoE(-/-)/LysMcre/TM(flox/flox)) were resistant to AAA formation induced by angiotensin II infusion, along with reduced macrophage infiltration, suppressed matrix metalloproteinase activities, and diminished oxidative stress.. Membrane-bound TM in macrophages plays an essential role in the development of AAA by enhancing proinflammatory mediator elaboration, macrophage recruitment, and oxidative stress.

Topics: Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortitis; Calcium Chloride; Cell Membrane; Cells, Cultured; Chemotaxis; Disease Models, Animal; Elastin; Human Umbilical Vein Endothelial Cells; Humans; Inflammation Mediators; Macrophages, Peritoneal; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Retrospective Studies; RNA Interference; Signal Transduction; Thrombomodulin; Time Factors; Transfection

The elastin peptide level (EP) and elastase-type activity (EA) were investigated in 89 patients with different types of systemic vasculitis (polyarteritis nodosa-14, non-specific aortoarteritis-33, temporal arteritis-23 and thromboangiitis obliterans-18) and compared to the controls: 31 patients with leg atherosclerosis and 12 aged subjects with no evident vascular pathology. EP and EA levels in patients with thromboangiitis obliterans were significantly lower as compared to leg atherosclerosis and the aged control group (p < 0.02 for EA, p < 0.05 for EP). The increase of EP predominated in giant-cell arteritis as compared to the other vasculitic groups (18/56 vs. 5/32, p < 0.05); EA in these patients was the lowest. The activation of elastin degradation after corticosteroid treatment was demonstrated by an increase of EP in temporal arteritis (p < 0.05) and of EA in thromboangiitis obliterans (p < 0.03). We suggest that the determination of the above parameters of elastin degradation may be helpful in the search for differences in mechanisms of vascular damage between atherosclerosis and inflammatory vascular diseases.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aortitis; Arteriosclerosis; Elastin; Female; Giant Cell Arteritis; Humans; Male; Middle Aged; Pancreatic Elastase; Peptides; Polyarteritis Nodosa; Reference Values; Thromboangiitis Obliterans

The predominant pathologic feature of abdominal aortic aneurysm is elastin destruction, and elastin destruction may be mediated by inflammation. In this investigation serial sections of abdominal aortic aneurysm specimens were selectively stained to study the relationship between inflammation and elastin degradation. In addition, soluble aortic extracts were examined for the presence of immunoglobulins. An inflammatory infiltrate was present in 8 of 10 of the abdominal aortic aneurysm specimens examined. The infiltrate was mononuclear, commonly located at the junction of the media and adventitia; it did not codistribute with loss of elastin. The presence of an inflammatory component in abdominal aortic aneurysm was associated with a large amount of immunoglobulin in soluble extracts from aneurysmal tissue compared to atherosclerotic and normal control extracts. This study further characterizes the microscopic pathology of abdominal aortic aneurysm and describes the presence of immunoglobulin in soluble tissue extracts. In addition, the possible role of inflammation in abdominal aortic aneurysm as it relates to protease expression is detailed.

Topics: Aorta, Abdominal; Aortic Aneurysm; Aortitis; Elastin; Humans; Immunoglobulins