Buschke-Ollendorff Syndrome Associated with Elevated Elastin Production by Affected Skin Fibroblasts in Culture

Buschke-Ollendorff syndrome (BOS; McKusick 16670) is an autosomal dominant connective-tissue disorder characterized by uneven osseous formation in bone (osteopoikilosis) and fibrous skin papules (dermatofibrosis lenticularis disseminata). We describe two patients in whom BOS occurred in an autosomal dominant inheritance pattern. The connective tissue of the skin lesions showed both collagen and elastin abnormalities by electron microscopy. Cultured fibroblasts from both patients produced 2–8 times more tropoelastin than normal skin fibroblasts in the presence of 10% calf serum. Involved skin flbroblasts of one patient produced up to eight times normal levels, whereas apparently uninvolved skin was also elevated more than threefold. In a second patient, whose involvement was nearly complete, elastin production was high in involved areas and less so in completely involved skin. Transforming growth factor-β1 (TGFβ1), a powerful stimulus for elastin production, brought about similar relative increases in normal and BOS strains. Basic fibroblast growth factor, an antagonist of TGFβ1-stimulated elastin production, was able to reduce elastin production in basal and TGFβ1 stimulated BOS strains. Elastin mRNA levels were elevated in all patient strains, suggesting that Buschke-Ollendorff syndrome may result, at least in part, from abnormal regulation of extracellular matrix metabolism that leads to increased steady-state levels of elastin mRNA and elastin accumulation in the dermis

Attenuation of fibrosis in vitro and in vivo with SPARC siRNA

INTRODUCTION: SPARC is a matricellular protein, which, along with other extracellular matrix components including collagens, is commonly over-expressed in fibrotic diseases. The purpose of this study was to examine whether inhibition of SPARC can regulate collagen expression in vitro and in vivo, and subsequently attenuate fibrotic stimulation by bleomycin in mouse skin and lungs. METHODS: In in vitro studies, skin fibroblasts obtained from a Tgfbr1 knock-in mouse (TBR1CA; Cre-ER) were transfected with SPARC siRNA. Gene and protein expressions of the Col1a2 and the Ctgf were examined by real-time RT-PCR and Western blotting, respectively. In in vivo studies, C57BL/6 mice were induced for skin and lung fibrosis by bleomycin and followed by SPARC siRNA treatment through subcutaneous injection and intratracheal instillation, respectively. The pathological changes of skin and lungs were assessed by hematoxylin and eosin and Masson\u27s trichrome stains. The expression changes of collagen in the tissues were assessed by real-time RT-PCR and non-crosslinked fibrillar collagen content assays. RESULTS: SPARC siRNA significantly reduced gene and protein expression of collagen type 1 in fibroblasts obtained from the TBR1CA; Cre-ER mouse that was induced for constitutively active TGF-beta receptor I. Skin and lung fibrosis induced by bleomycin was markedly reduced by treatment with SPARC siRNA. The anti-fibrotic effect of SPARC siRNA in vivo was accompanied by an inhibition of Ctgf expression in these same tissues. CONCLUSIONS: Specific inhibition of SPARC effectively reduced fibrotic changes in vitro and in vivo. SPARC inhibition may represent a potential therapeutic approach to fibrotic diseases

Association of comorbidity burden with abnormal cardiac mechanics: Findings from the HyperGEN study

BACKGROUND: Comorbidities are common in heart failure (HF), and the number of comorbidities has been associated with poor outcomes in HF patients. However, little is known about the effect of multiple comorbidities on cardiac mechanics, which could impact the pathogenesis of HF. We sought to determine the relationship between comorbidity burden and adverse cardiac mechanics. METHODS AND RESULTS: We performed speckle‐tracking analysis on echocardiograms from the HyperGEN study (n=2150). Global longitudinal, circumferential, and radial strain, and early diastolic (e') tissue velocities were measured. We evaluated the association between comorbidity number and cardiac mechanics using linear mixed effects models to account for relatedness among subjects. The mean age was 51±14 years, 58% were female, and 47% were African American. Dyslipidemia and hypertension were the most common comorbidities (61% and 58%, respectively). After adjusting for left ventricular (LV) mass index, ejection fraction, and several potential confounders, the number of comorbidities remained associated with all indices of cardiac mechanics except global circumferential strain (eg, β=−0.32 [95% CI −0.44, −0.20] per 1‐unit increase in number of comorbidities for global longitudinal strain; β=−0.16 [95% CI −0.20, −0.11] for e' velocity; P≤0.0001 for both comparisons). Results were similar after excluding participants with abnormal LV geometry (P<0.05 for all comparisons). CONCLUSIONS: Higher comorbidity burden is associated with worse cardiac mechanics, even in the presence of normal LV geometry. The deleterious effect of multiple comorbidities on cardiac mechanics may explain both the high comorbidity burden and adverse outcomes in patients who ultimately develop HF

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms.

OBJECTIVE: This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm in patients with Marfan syndrome, familial thoracic aortic aneurysm, or nonfamilial thoracic aortic aneurysm. BACKGROUND: Thoracic aortic aneurysms are associated with a pathologic lesion termed medial degeneration, which is described as a noninflammatory lesion. Thoracic aortic aneurysms are a complication of Marfan syndrome and can be inherited in an autosomal dominant manner of familial thoracic aortic aneurysm. METHODS: Full aortic segments were collected from patients undergoing elective repair with Marfan syndrome (n = 5), familial thoracic aortic aneurysm (n = 6), and thoracic aortic aneurysms (n = 9), along with control aortas (n = 5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time polymerase chain reaction analysis was performed to quantify the expression level of the T-cell receptor beta-chain variable region gene. RESULTS: Immunohistochemistry of thoracic aortic aneurysm aortas demonstrated that the media and adventitia from Marfan syndrome, familial thoracic aortic aneurysm, and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient\u27s age at the time of prophylactic surgical repair of the aorta. T-cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had Marfan syndrome, familial thoracic aortic aneurysm, or sporadic disease. CONCLUSION: These results indicate that the infiltration of inflammatory cells contributes to the pathogenesis of thoracic aortic aneurysms. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of patients with thoracic aortic aneurysms may contribute to the initial immune response