One of the most prevalent pollutants in urban cities is diesel exhaust particulate (DEP). Air pollution has been linked with increased risk of recurrent myocardial infarction (MI) and MI related death (Brook, 2008). This may be due, in part, to effects on atherosclerotic plaque stability and blood clotting tendency. Whether exposure to DEP changes the response of the heart to ischaemia, resulting in increased damage after MI is less well documented. The work described in this thesis was designed to investigate the hypothesis that pulmonary instillation of DEP would increase vulnerability of the heart to subsequent myocardial reperfusion injury secondary to activation of a systemic inflammatory response, endothelial dysfunction and triggering of transient receptor potential vanilloid 1 (TRPV1) mediated autonomic reflexes in the lung. Examination of bronchoalveolar lavage (BAL) fluid revealed pulmonary inflammation 6 h after exposure to DEP, characterised by neutrophil infiltration, raised levels of the inflammatory mediator interleukin-6 (IL-6) and an increase in alveolar permeability demonstrated by increased levels of protein in the lavage fluid. Pulmonary inflammation was largely resolved 24 h after exposure. While there was no indication of systemic inflammation at 6 h after DEP instillation, the levels of two inflammatory mediators, IL-6 and tumour necrosis factor alpha (TNFα) were increased in the plasma by 24 h after exposure. DEP had no affect on blood flow responses to the endothelium dependent dilator acetylcholine (ACh) in rat hind-limb vasculature in vivo at 6 or 24 h. In summary, while exposure of rats to DEP can induce both pulmonary and systemic inflammation, it does not modify endothelium-dependent vasodilatation. Ischaemia-reperfusion (I/R) was induced in vivo in anaesthetised rats and ex vivo in buffer perfused hearts from rats that had received DEP in vivo 6 h earlier. In both in vivo and ex vivo I/R models, infarct size (unstained by triphenyltetrazolium choride) was significantly increased in hearts from DEP-instilled rats relative to hearts from saline-instilled or non-instilled rats. Baseline oxidant stress, determined by electron paramagnetic spin resonance (EPR) in heart perfusate, was also significantly higher in perfusate of hearts from DEP-instilled rats. In summary, a single exposure of the lung to DEP leads to priming of the myocardium for I/R injury. As the results cited above illustrated, priming of hearts appeared unlikely to be due to either coronary vascular endothelial dysfunction or systemic inflammation. At 6 h post exposure, DEP was associated with increased blood pressure and myocardial hypersensitivity to ischaemia-induced arrhythmias, both suggestive of sympathetic activation. The beta 1 (β1) selective blocker metoprolol was used to investigate the role of the sympathetic nervous system (SNS) in transmitting the influence of DEP in the lung to the myocardium via β1 adrenoceptor activation. Administration of metoprolol (10 mg/kg, intraperotineal) at the time of DEP instillation into the lung was found to protect the heart from potentiation of ex vivo reperfusion injury. Metoprolol was also effective in reducing oxygen free radical generation from these hearts. The TRPV1 antagonist AMG 9810 was also used to study the role of TRPV1 receptors in mediating the priming influence of pulmonary DEP to the myocardium since activation of sensory receptors have been reported to modify sympathetic output via feedback to the central nervous system (Widdicombe et al., 2001). Coadministration of AMG 9810 (30 mg/kg) in vivo with DEP into the lung was found to prevent enhancement of ex vivo reperfusion injury associated with DEP instillation alone. Collectively these results have demonstrated that a single exposure of the lung to DEP leads to priming of the myocardium for I/R injury. Furthermore, this priming occurs via activation of a pulmonary sensory reflex that is likely to involve secondary activation of systemic β1 adrenoceptors.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:586487 |
| Date | January 2013 |
| Creators | Robertson, Sarah |
| Contributors | Gray, Alasdair; Hadoke, Patrick; Miller, Mark; Gray, Gillian |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/8180 |
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