Cigarette Smoke Toxins Deposited on Surfaces: Implications for Human Health

Cigarette smoking remains a significant health threat for smokers and nonsmokers alike. Secondhand smoke (SHS) is intrinsically more toxic than directly inhaled smoke. Recently, a new threat has been discovered – Thirdhand smoke (THS) – the accumulation of SHS on surfaces that ages with time, becoming progressively more toxic. THS is a potential health threat to children, spouses of smokers and workers in environments where smoking is or has been allowed. The goal of this study is to investigate the effects of THS on liver, lung, skin healing, and behavior, using an animal model exposed to THS under conditions that mimic exposure of humans. THS-exposed mice show alterations in multiple organ systems and excrete levels of NNAL (a tobacco-specific carcinogen biomarker) similar to those found in children exposed to SHS (and consequently to THS). In liver, THS leads to increased lipid levels and non-alcoholic fatty liver disease, a precursor to cirrhosis and cancer and a potential contributor to cardiovascular disease. In lung, THS stimulates excess collagen production and high levels of inflammatory cytokines, suggesting propensity for fibrosis with implications for inflammation-induced diseases such as chronic obstructive pulmonary disease and asthma. In wounded skin, healing in THS-exposed mice has many characteristics of the poor healing of surgical incisions observed in human smokers. Lastly, behavioral tests show that THS-exposed mice become hyperactive. The latter data, combined with emerging associated behavioral problems in children exposed to SHS/THS, suggest that, with prolonged exposure, they may be at significant risk for developing more severe neurological disorders. These results provide a basis for studies on the toxic effects of THS in humans and inform potential regulatory policies to prevent involuntary exposure to THS

Membrane-type 1 matrix metalloproteinase expression by hepatic stellate cells : its role in liver fibrosis

Hepatic stellate cells (HSC) play a central role in the development of liver fibrosis, by both production of extracellular matrix proteins and through the secretion of the matrix degrading metalloproteinases, including gelatinase A. Gelatinase A is activated by a unique mechanism involving membrane - type 1 matrix metalloproteinase (MT1-MMP) and tissue inhibitor of metalloproteinase - 2 (TIMP-2) at the cell surface. It has been suggested that decreased 'activation' of gelatinase A is a possible mechanism for the progression of fibrosis. This thesis describes the synthesis and regulation of MT1-MMP by rat HSC and correlates this with gelatinase A activation. It goes on to study MT1-MMP expression in a rat model of liver fibrosis.HSC isolated from normal human and rat liver, by Northern analysis HSC were found to express MT1-MMP mRNA. With time in culture on plastic MT1-MMP mRNA expression was increased, relative to β-actin, 6-fold and correlated temporally with the activation of gelatinase A as seen by gelatin zymography. Upregulation of MT1-MMP mRNA expression and gelatinase A activation was seen with both Concavalin A and TNF-α. Western immunoblotting confirmed MT1-MMP protein to the membrane fraction of HSC.By ribonuclease protection assay MT1-MMP, gelatinase A and TIMP-2 mRNA were found to be upregulated, relative to normal, in cirrhotic rat liver. This correlated with increased amounts of 'activated' gelatinase A being found by gelatine zymography.In contrary to previous ideas a link was therefore developed between the activation mechanism of gelatinase A and the development of liver fibrosis. Further studies were conducted on the association between gelatinase A and HSC proliferation in culture. By 3 independent methods either gelatinase A expression or its activity was inhibited and a significant reduction in proliferation was noted.These data suggest that MT1-MMP, by its activation of gelatinase A, may play a role in the development of liver fibrosis.</p

Expression of matrix metalloproteinase-2 and -14 persists during early resolution of experimental liver fibrosis and might contribute to fibrolysis

Abstract: Background/Aims: Resolution of liver fibrosis is possible but the identity of the matrix metalloproteinases (MMPs) which degrade the accumulated collagens is uncertain. We examined MMP-2 and MMP-14 expression in established and resolving fibrosis to assess their role in resolution of liver fibrosis.Methods: MMP and tissue inhibitor of metalloproteinase (TIMP)-2 expression in liver extracts was examined by ribonuclease protection assay, Western blotting and gelatin zymography. MMP activity was examined by 14C gelatin degradation.Results: In human cirrhotic liver, MMP-14 mRNA was increased to 230–330% of normal liver expression. Both 63 kDa proenzyme and 60 kDa activated form were present. Cirrhotic livers had 270–320% of normal liver expression of MMP-2 protein with 20–25% being the 62 Da activated form. Protein and mRNA for MMP-2 and MMP-14 progressively increased during 8 weeks of CCl4 treatment in rats. Between 3 and 7 days of resolution from CCl4 liver fibrosis, MMP-2 and MMP-14 persisted at elevated levels. Gelatinolytic activity in liver homogenates peaked at 7 days of recovery, being 140% above that in livers at peak fibrosis.Conclusions: Increased expression and activation of MMP-2 and -14 occurs even under conditions of elevated TIMPs during liver fibrogenesis. During liver fibrosis resolution, as TIMP expression decays, the persistence of MMP-2 and MMP-14 may permit collagen degradation

Engineering Online and In-Person Social Networks for Physical Activity: A Randomized Trial

Social networks can influence physical activity, but little is known about how best to engineer online and in-person social networks to increase activity

Engineering online and in-person social networks to sustain physical activity: Application of a conceptual model

Background: High rates of physical inactivity compromise the health status of populations globally. Social networks have been shown to influence physical activity (PA), but little is known about how best to engineer social networks to sustain PA. To improve procedures for building networks that shape PA as a normative behavior, there is a need for more specific hypotheses about how social variables influence PA. There is also a need to integrate concepts from network science with ecological concepts that often guide the design of in-person and electronically-mediated interventions. Therefore, this paper: (1) proposes a conceptual model that integrates principles from network science and ecology across in-person and electronically-mediated intervention modes; and (2) illustrates the application of this model to the design and evaluation of a social network intervention for PA. Methods/Design: A conceptual model for engineering social networks was developed based on a scoping literature review of modifiable social influences on PA. The model guided the design of a cluster randomized controlled trial in which 308 sedentary adults were randomly assigned to three groups: WalkLink+: prompted and provided feedback on participants’ online and in-person social-network interactions to expand networks for PA, plus provided evidence-based online walking program and weekly walking tips; WalkLink: evidence-based online walking program and weekly tips only; Minimal Treatment Control: weekly tips only. The effects of these treatment conditions were assessed at baseline, post-program, and 6-month follow-up. The primary outcome was accelerometer-measured PA. Secondary outcomes included objectively-measured aerobic fitness, body mass index, waist circumference, blood pressure, and neighborhood walkability; and self-reported measures of the physical environment, social network environment, and social network interactions. The differential effects of the three treatment conditions on primary and secondary outcomes will be analyzed using general linear modeling (GLM), or generalized linear modeling if the assumptions for GLM cannot be met. Discussion: Results will contribute to greater understanding of how to conceptualize and implement social networks to support long-term PA. Establishing social networks for PA across multiple life settings could contribute to cultural norms that sustain active living