Faculty Bibliography

Advanced age is characterized by impairments in wound healing, and evidence is accumulating that this may be due in part to a concomitant increase in oxidative stress. Extended exposure to reactive oxygen species (ROS) is thought to lead to cellular dysfunction and organismal death via the destructive oxidation of intra-cellular proteins, lipids and nucleic acids. Extracellular superoxide dismutase (ecSOD/SOD3) is a prime antioxidant enzyme in the extracellular space that eliminates ROS. Here, we demonstrate that reduced SOD3 levels contribute to healing impairments in aged mice. These impairments include delayed wound closure, reduced neovascularization, impaired fibroblast proliferation and increased neutrophil recruitment. We further establish that SOD3 KO and aged fibroblasts both display reduced production of TGF-beta1, leading to decreased differentiation of fibroblasts into myofibroblasts. Taken together, these results suggest that wound healing impairments in ageing are associated with increased levels of ROS, decreased SOD3 expression and impaired extracellular oxidative stress regulation. Our results identify SOD3 as a possible target to correct age-related cellular dysfunction in wound healing.

BACKGROUND: While low dose computed tomography (LDCT) screening for lung cancer is recommended for high-risk smokers, ages 55-74 years, information about asbestos exposure may not be routinely elicited. Asbestos exposure is associated with declining respiratory function over time; however, the effect of a history of asbestos exposure in LDCT screening cohorts is limited. We report the relationship between asbestos exposure and pulmonary function in a cohort of heavy smokers with a history of occupational asbestos exposure, hypothesizing that these subjects will have additional decreased pulmonary function. We also examined relationships between spirometric measurements and the presence of isolated pleural plaques. METHODS: A cross-sectional study was performed using data from the NYU Lung Cancer Biomarker Center cohort to compare study subjects with a history asbestos exposure primarily in the period since 1970 when tighter federal standards were in place (n = 359) to those without asbestos exposure (n = 1038) with respect to pulmonary function, LDCT lung imaging findings, and clinical symptoms. We further classified individuals with asbestos exposure by length of exposure time to examine the effect of duration of exposure on pulmonary function. Lastly, for asbestos-exposed participants, we examined the association of spirometric measurements with the presence of absence of isolated pleural plaques. RESULTS: Individuals with asbestos exposure had decreased FVC % predicted compared to those with no asbestos exposure (76% vs. 85% predicted, P < 0.01) and FEV1 % predicted (64% vs. 67% predicted, P < 0.01). Since there was no change in FEV1 /FVC ratio, the findings are consistent with restrictive impairment. Those with >/=20 years of exposure had a lower mean FVC % predicted compared to those with less than 20 years of exposure (74% vs. 78% predicted, P = 0.017). Individuals with asbestos exposure were more likely to have pleural plaques (P < 0.001) on CT. Those with isolated pleural plaques had lower mean % predicted FEV1 (P = 0.005) and FVC (P = 0.001) compared to those without pleural plaques. CONCLUSIONS: Occupational asbestos exposure in a cohort of heavy smokers was associated with a significant restrictive decline in pulmonary function, with longer duration of exposure associated with greater decline. The presence of isolated pleural plaques was also associated with reduced lung function. Am. J. Ind. Med. 9999:1-8, 2016. (c) 2016 Wiley Periodicals, Inc.

Birds have a distally reduced, splinter-like fibula that is shorter than the tibia. In embryonic development, both skeletal elements start out with similar lengths. We examined molecular markers of cartilage differentiation in chicken embryos. We found that the distal end of the fibula expresses Indian hedgehog (IHH), undergoing terminal cartilage differentiation, and almost no Parathyroid-related protein (PTHrP), which is required to develop a proliferative growth plate (epiphysis). Reduction of the distal fibula may be influenced earlier by its close contact with the nearby fibulare, which strongly expresses PTHrP. The epiphysis-like fibulare however then separates from the fibula, which fails to maintain a distal growth plate, and fibular reduction ensues. Experimental downregulation of IHH signaling at a postmorphogenetic stage led to a tibia and fibula of equal length: The fibula is longer than in controls and fused to the fibulare, whereas the tibia is shorter and bent. We propose that the presence of a distal fibular epiphysis may constrain greater growth in the tibia. Accordingly, many Mesozoic birds show a fibula that has lost its distal epiphysis, but remains almost as long as the tibia, suggesting that loss of the fibulare preceded and allowed subsequent evolution of great fibulo-tibial disparity.

OBJECTIVE: We hypothesized that the hypoxia-inducible factor (HIF) 1alpha in vascular smooth muscle contributes to the development of atherosclerosis, and links intravascular pressure to this process. APPROACH AND RESULTS: Transverse aortic constriction was used to create high-pressure vascular segments in control, apolipoprotein E (ApoE)-/-, smooth muscle-HIF1alpha-/-, and ApoE-/-xsmooth muscle-HIF1alpha-/- double-knockout mice. Transverse aortic constriction selectively induced atherosclerosis in high-pressure vascular segments in young ApoE-/- mice on normal chow, including coronary plaques within 1 month. Concomitant deletion of HIF1alpha from smooth muscle significantly reduced vascular inflammation, and attenuated atherosclerosis. CONCLUSIONS: HIF1alpha in vascular smooth muscle plays an important role in the pathogenesis of atherosclerosis, and may provide a mechanistic link between blood pressure, vascular inflammation, and lipid deposition.

The epithelial Na channel (ENaC) forms a pathway for Na(+) reabsorption in the distal nephron, and regulation of these channels is essential for salt homeostasis. In the rat kidney, ENaC subunits reached the plasma membrane in both immature and fully processed forms, the latter defined by either endoglycosidase H-insensitive glycosylation or proteolytic cleavage. Animals adapted to a low-salt diet have increased ENaC surface expression that is specific for the mature forms of the subunit proteins and is similar (three- to fourfold) for alpha, beta, and gammaENaC. Kidney membranes were fractionated using differential centrifugation, sucrose-gradient separation, and immunoabsorption. Endoplasmic reticulum membranes, isolated using an antibody against calnexin, expressed immature gammaENaC, and the content decreased with Na depletion. Golgi membranes, isolated with an antibody against the cis-Golgi protein GM130, expressed both immature and processed gammaENaC; Na depletion increased the content of processed gammaENaC in this fraction by 3.8-fold. An endosomal compartment isolated using an antibody against Rab11 contained both immature and processed gammaENaC; the content of processed subunit increased 2.4-fold with Na depletion. Finally, we assessed the content of gammaENaC in the late endocytic compartments indirectly using urinary exosomes. All of the gammaENaC in these exosomes was in the fully cleaved form, and its content increased by 4.5-fold with Na depletion. These results imply that stimulation of ENaC surface expression results at least in part from increased rates of formation of fully processed subunits in the Golgi and subsequent trafficking to the apical membrane.

Although counteracting innate defenses allows oncolytic viruses (OVs) to better replicate and spread within tumors, CD8(+) T-cells restrict their capacity to trigger systemic anti-tumor immune responses. Herpes simplex virus-1 (HSV-1) evades CD8(+) T-cells by producing ICP47, which limits immune recognition of infected cells by inhibiting the transporter associated with antigen processing (TAP). Surprisingly, removing ICP47 was assumed to benefit OV immuno-therapy, but the impact of inhibiting TAP remains unknown because human HSV-1 ICP47 is not effective in rodents. Here, we engineer an HSV-1 OV to produce bovine herpesvirus UL49.5, which unlike ICP47, antagonizes rodent and human TAP. Significantly, UL49.5-expressing OVs showed superior efficacy treating bladder and breast cancer in murine models that was dependent upon CD8(+) T-cells. Besides injected subcutaneous tumors, UL49.5-OV reduced untreated, contralateral tumor size and metastases. These findings establish TAP inhibitor-armed OVs that evade CD8(+) T-cells as an immunotherapy strategy to elicit potent local and systemic anti-tumor responses.

Radiation therapy is a mainstay in the treatment of many malignancies, but also results in collateral obliteration of microvasculature and dermal/subcutaneous fibrosis. Soft tissue reconstruction of hypovascular, irradiated recipient sites through fat grafting remains challenging, however a coincident improvement in surrounding skin quality has been noted. Cell-assisted lipotransfer (CAL), the enrichment of fat with additional adipose-derived stem cells (ASCs) from the stromal vascular fraction, has been shown to improve fat volume retention, and enhanced outcomes may also be achieved with CAL at irradiated sites. Supplementing fat grafts with additional ASCs may also augment the regenerative effect on radiation-damaged skin. In this study, we demonstrate the ability for CAL to enhance fat graft volume retention when placed beneath the irradiated scalps of immunocompromised mice. Histologic metrics of fat graft survival were also appreciated, with improved structural qualities and vascularity. Finally, rehabilitation of radiation-induced soft tissue changes were also noted, as enhanced amelioration of dermal thickness, collagen content, skin vascularity, and biomechanical measures were all observed with CAL compared to unsupplemented fat grafts. Supplementation of fat grafts with ASCs therefore shows promise for reconstruction of complex soft tissue defects following adjuvant radiotherapy

Brain-derived neurotrophic factor (BDNF) plays an important role in neurodevelopment, synaptic plasticity, learning and memory, and in preventing neurodegeneration. Despite decades of investigations into downstream signaling cascades and changes in cellular processes, the mechanisms of how BDNF reshapes circuits in vivo remain unclear. This informational gap partly arises from the fact that the bulk of studies into the molecular actions of BDNF have been performed in dissociated neuronal cultures, while the majority of studies on synaptic plasticity, learning and memory were performed in acute brain slices or in vivo. A recent study by Bowling-Bhattacharya et al., measured the proteomic changes in acute adult hippocampal slices following treatment and reported changes in proteins of neuronal and non-neuronal origin that may in concert modulate synaptic release and secretion in the slice. In this paper, we place these findings into the context of existing literature and discuss how they impact our understanding of how BDNF can reshape the brain.