Radiation-induced skin injury in the animal model of scleroderma: implications for post-radiotherapy fibrosis

<p>Abstract</p> <p>Background</p> <p>Radiation therapy is generally contraindicated for cancer patients with collagen vascular diseases (CVD) such as scleroderma due to an increased risk of fibrosis. The tight skin (TSK) mouse has skin which, in some respects, mimics that of patients with scleroderma. The skin radiation response of TSK mice has not been previously reported. If TSK mice are shown to have radiation sensitive skin, they may prove to be a useful model to examine the mechanisms underlying skin radiation injury, protection, mitigation and treatment.</p> <p>Methods</p> <p>The hind limbs of TSK and parental control C57BL/6 mice received a radiation exposure sufficient to cause approximately the same level of acute injury. Endpoints included skin damage scored using a non-linear, semi-quantitative scale and tissue fibrosis assessed by measuring passive leg extension. In addition, TGF-β1 cytokine levels were measured monthly in skin tissue.</p> <p>Results</p> <p>Contrary to our expectations, TSK mice were more resistant (i.e. 20%) to radiation than parental control mice. Although acute skin reactions were similar in both mouse strains, radiation injury in TSK mice continued to decrease with time such that several months after radiation there was significantly less skin damage and leg contraction compared to C57BL/6 mice (p < 0.05). Consistent with the expected association of transforming growth factor beta-1 (TGF-β1) with late tissue injury, levels of the cytokine were significantly higher in the skin of the C57BL/6 mouse compared to TSK mouse at all time points (p < 0.05).</p> <p>Conclusion</p> <p>TSK mice are not recommended as a model of scleroderma involving radiation injury. The genetic and molecular basis for reduced radiation injury observed in TSK mice warrants further investigation particularly to identify mechanisms capable of reducing tissue fibrosis after radiation injury.</p

Low fingertip temperature rebound measured by digital thermal monitoring strongly correlates with the presence and extent of coronary artery disease diagnosed by 64-slice multi-detector computed tomography

Previous studies showed strong correlations between low fingertip temperature rebound measured by digital thermal monitoring (DTM) during a 5 min arm-cuff induced reactive hyperemia and both the Framingham Risk Score (FRS), and coronary artery calcification (CAC) in asymptomatic populations. This study evaluates the correlation between DTM and coronary artery disease (CAD) measured by CT angiography (CTA) in symptomatic patients. It also investigates the correlation between CTA and a new index of neurovascular reactivity measured by DTM. 129 patients, age 63 ± 9 years, 68% male, underwent DTM, CAC and CTA. Adjusted DTM indices in the occluded arm were calculated: temperature rebound: aTR and area under the temperature curve aTMP-AUC. DTM neurovascular reactivity (NVR) index was measured based on increased fingertip temperature in the non-occluded arm. Obstructive CAD was defined as ≥50% luminal stenosis, and normal as no stenosis and CAC = 0. Baseline fingertip temperature was not different across the groups. However, all DTM indices of vascular and neurovascular reactivity significantly decreased from normal to non-obstructive to obstructive CAD [(aTR 1.77 ± 1.18 to 1.24 ± 1.14 to 0.94 ± 0.92) (P = 0.009), (aTMP-AUC: 355.6 ± 242.4 to 277.4 ± 182.4 to 184.4 ± 171.2) (P = 0.001), (NVR: 161.5 ± 147.4 to 77.6 ± 88.2 to 48.8 ± 63.8) (P = 0.015)]. After adjusting for risk factors, the odds ratio for obstructive CAD compared to normal in the lowest versus two upper tertiles of FRS, aTR, aTMP-AUC, and NVR were 2.41 (1.02–5.93), P = 0.05, 8.67 (2.6–9.4), P = 0.001, 11.62 (5.1–28.7), P = 0.001, and 3.58 (1.09–11.69), P = 0.01, respectively. DTM indices and FRS combined resulted in a ROC curve area of 0.88 for the prediction of obstructive CAD. In patients suspected of CAD, low fingertip temperature rebound measured by DTM significantly predicted CTA-diagnosed obstructive disease

Fibulin-5, an integrin-binding matricellular protein: its function in development and disease

Interactions between the extracellular matrix (ECM) and cells are critical in embryonic development, tissue homeostasis, physiological remodeling, and tumorigenesis. Matricellular proteins, a group of ECM components, mediate cell-ECM interactions. One such molecule, Fibulin-5 is a 66-kDa glycoprotein secreted by various cell types, including vascular smooth muscle cells (SMCs), fibroblasts, and endothelial cells. Fibulin-5 contributes to the formation of elastic fibers by binding to structural components including tropoelastin and fibrillin-1, and to cross-linking enzymes, aiding elastic fiber assembly. Mice deficient in the fibulin-5 gene (Fbln5) exhibit systemic elastic fiber defects with manifestations of loose skin, tortuous aorta, emphysematous lung and genital prolapse. Although Fbln5 expression is down-regulated after birth, following the completion of elastic fiber formation, expression is reactivated upon tissue injury, affecting diverse cellular functions independent of its elastogenic function. Fibulin-5 contains an evolutionally conserved arginine-glycine-aspartic acid (RGD) motif in the N-terminal region, which mediates binding to a subset of integrins, including α5β1, αvβ3, and αvβ5. Fibulin-5 enhances substrate attachment of endothelial cells, while inhibiting migration and proliferation in a cell type- and context-dependent manner. The antagonistic function of fibulin-5 in angiogenesis has been demonstrated in vitro and in vivo; fibulin-5 may block angiogenesis by inducing the anti-angiogenic molecule thrompospondin-1, by antagonizing VEGF165-mediated signaling, and/or by antagonizing fibronectin-mediated signaling through directly binding and blocking the α5β1 fibronectin receptor. The overall effect of fibulin-5 on tumor growth depends on the balance between the inhibitory property of fibulin-5 on angiogenesis and the direct effect of fibulin-5 on proliferation and migration of tumor cells. However, the effect of tumor-derived versus host microenvironment-derived fibulin-5 remains to be evaluated