How does pulmonary exposure to particulate matter predispose the heart to increased injury after myocardial infarction?
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Date
06/07/2013Author
Robertson, Sarah
Metadata
Abstract
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.