elastin and Vasculitis

The perforating dermatoses are a group of disorders characterized by transepidermal elimination of a material from the upper dermis. The most widely accepted classification consists of four primary perforating disorders that are defined by the type of material eliminated and the type of epidermal disruption. Pathogenesis of the perforating dermatoses is poorly understood, but some appear to have a genetic component. There are also acquired forms, which have been associated with underlying systemic diseases and the use of certain drugs. In this report, we describe a perforating disorder that occurred secondary to leflunomide therapy. To our knowledge, this is the first case in which this has been reported. We also review the recent literature on medications associated with perforating disorders.

Topics: Adult; Drug Eruptions; Elastin; Epidermis; Female; Humans; Immunosuppressive Agents; Leflunomide; Skin Diseases; Vasculitis

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

Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch, and aortic stiffening in hypertension remains undefined.. Our aim was to determine the role of inflammation and mechanical stretch in aortic stiffening.. Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson trichrome blue staining and biochemically by hydroxyproline content, in wild-type but not in recombination activating gene-1-deficient mice. Aortic compliance, defined by ex vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in wild-type mice (P<0.01) but not in recombination activating gene-1-deficient mice (P<0.05). Adoptive transfer of T-cells to recombination activating gene-1-deficient mice restored aortic collagen deposition and stiffness to values observed in wild-type mice. Mice lacking the T-cell-derived cytokine interleukin 17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T-cell infiltration, aortic stiffening, and collagen deposition. Finally, we found that mechanical stretch induces the expression of collagen 1α1, 3α1, and 5a1 in cultured aortic fibroblasts in a p38 mitogen-activated protein kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. Interleukin 17a also induced collagen 3a1 expression via the activation of p38 mitogen-activated protein kinase.. Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.

Topics: Adoptive Transfer; Angiotensin II; Animals; Aortic Diseases; CD4 Antigens; CD8 Antigens; Cells, Cultured; Collagen; Disease Models, Animal; Elastin; Fibroblasts; Homeodomain Proteins; Hypertension; Inflammation; Interleukin-17; Male; Mice; Mice, Knockout; p38 Mitogen-Activated Protein Kinases; Stress, Mechanical; T-Lymphocytes; Vascular Stiffness; Vasculitis; Vasoconstrictor Agents

To study how the balance between tacrolimus elution and polymer degradation from drug-eluting stents (DES) affects neointimal thickening (NIT) in swine coronary arteries.. We assessed a fast-degrading high dose (2 microg/mm2), a slow degrading low dose (1 microg/mm2) or polymer-only coated DES (Pol) versus bare metal stent (BMS). Coronary segments were pre-injured with a balloon/artery ratio of 1.1 to 1.3. Then stents were implanted at that site with a stent/artery ratio of 1.1, with a follow-up period of 5 to 180 days. Histology showed a well endothelialised neointima (82 +/- 1% in high dose DES vs. 93 +/- 8% in BMS) already at five days, without differences in eNOS expression. Morphometry indicated that neointimal thickness in DES was significantly reduced as compared to BMS and Pol at 28 and 90 days. Polymer degradation products induced a distinct inflammatory response which was effectively suppressed in DES. Between 90 and 180 days, however, the slow degrading low-dose stent showed catch-up of NIT.. Tacrolimus eluted from a biodegradable stent coating can suppress the inflammatory effect of the coating degradation products if the balance between the drug levels and the degradation products is favorable.

Topics: Angioplasty, Balloon, Coronary; Animals; Coated Materials, Biocompatible; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Elastin; Endothelium, Vascular; Immunohistochemistry; Immunosuppressive Agents; Lactic Acid; Metals; Nitric Oxide Synthase Type III; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Sus scrofa; Swine; Swine, Miniature; Tacrolimus; Tunica Intima; Tunica Media; Vasculitis

Collagens are abundant within the atherosclerotic plaque, where they contribute to lesion volume and mechanical stability and influence cell signaling. The discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds to collagen, is expressed in blood vessels, but evidence for a functional role during atherogenesis is incomplete. In the present study, we generated Ddr1(+/+);Ldlr(-/-) and Ddr1(-/-);Ldlr(-/-) mice and fed them an atherogenic diet for 12 or 24 weeks. Targeted deletion of Ddr1 resulted in a 50% to 60% reduction in atherosclerotic lesion area in the descending aorta at both 12 and 24 weeks. Ddr1(-/-);Ldlr(-/-) plaques exhibited accelerated deposition of fibrillar collagen and elastin at 12 weeks compared with Ddr1(+/+);Ldlr(-/-) plaques. Expression analysis of laser microdissected lesions in vivo, and of Ddr1(-/-) smooth muscle cells in vitro, revealed increased mRNA levels for procollagen alpha1(I) and alpha1(III) and tropoelastin, suggesting an enhancement of matrix synthesis in the absence of DDR1. Furthermore, whereas plaque smooth muscle cell content was unchanged, Ddr1(-/-);Ldlr(-/-) plaques had a 49% decrease in macrophage content at 12 weeks, with a concomitant reduction of in situ gelatinolytic activity. Moreover, mRNA expression of both monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 was reduced in vivo, and Ddr1(-/-);Ldlr(-/-) macrophages demonstrated impaired matrix metalloproteinase expression in vitro. These data suggest novel roles for DDR1 in macrophage recruitment and invasion during atherogenesis. In conclusion, our data support a role for DDR1 in the regulation of both inflammation and fibrosis early in plaque development. Deletion of DDR1 attenuated atherogenesis and resulted in the formation of matrix-rich plaques.

Topics: Animals; Aorta, Thoracic; Atherosclerosis; Chemokine CCL2; Collagen; Diet, Atherogenic; Discoidin Domain Receptors; Disease Models, Animal; Elastin; Extracellular Matrix; Female; Fibrosis; Lipids; Macrophages; Male; Mice; Mice, Mutant Strains; Muscle, Smooth, Vascular; Mutagenesis; Receptor Protein-Tyrosine Kinases; Receptors, LDL; Receptors, Mitogen; Vascular Cell Adhesion Molecule-1; Vasculitis