Airway resistance, inflammation and oxidative stress following exposure to diesel exhaust particle in angiotensin II-induced hypertension in mice

Abstract

Exposure to particulate matter is a risk factor for respiratory and cardiovascular diseases. However, the mechanisms underlying these effects are not well understood. Here, we compared the impact of diesel exhaust particles (DEP) on airway resistance, inflammation and oxidative stress in normal mice, or mice made hypertensive by implanting osmotic minipump infusing angiotensin II. On day 13 after the onset of infusion, angiotensin II induced significant increase in heart rate (P < 0.05) and systolic blood pressure (P < 0.0001). On the same day, mice were intratracheally instilled with either DEP (15 μg/mouse) or saline. Twenty-four hour later, the measurement of airway reactivity to methacholine (0–10 mg/ml) in vivo by a forced oscillation technique showed a significant and dose dependent increase in airway resistance in normotensive mice exposed to DEP compared to those exposed to saline. In hypertensive mice, there was no difference in airway resistance in DEP versus saline exposed mice. However, following exposure to DEP, airway resistance significantly increased in normotensive versus hypertensive mice. Bronchoalveolar lavage (BAL) fluid analysis showed a significant increase in macrophage numbers in normotensive mice exposed to DEP compared to those exposed to saline, and to hypertensive mice exposed to DEP. Neutrophil numbers were significantly increased in both normotensive and hypertensive mice exposed to DEP compared with their respective control groups. Superoxide dismutase activity was significantly decreased following DEP exposure in both normotensive and hypertensive mice compared to their respective controls. However, total proteins, a marker for increase of epithelial permeability, and malondialdehyde, a reflection of lipid peroxidation, were only increased in normotensive mice exposed to DEP. Therefore, our data suggest that DEP do not aggravate airway resistance and inflammation in angiotensin II-induced hypertensive mice. On the contrary, at the dose of DEP and time point investigated, airway resistance, inflammation and oxidative stress are increased in normotensive compared to hypertensive mice.

Introduction

Substantial epidemiological studies demonstrated that daily average exposures to particulate matter can cause acute respiratory and cardiovascular effects (Brook et al., 2010). Diesel exhaust particles (DEP) are the major particulate matter of air pollution and comprise a nanoparticulate carbonaceous core, multiple organic components such as polyaromatic hydrocarbons, transition metals, and adsorbed materials such as pollen and dust (Boland et al., 1999). Their small size favors their deposition in the lung with a portion depositing in the alveoli and entering the pulmonary and systemic circulation (Boland et al., 1999, Nemmar et al., 2002). Acute inhalation of DEP in healthy individuals, and those with preexisting cardiovascular and respiratory disease, results in respiratory toxicity with consequent development of lung edema, infiltration of polymorphonuclear leukocytes, and the production of proinflammatory cytokines and reactive oxygen species (Salvi et al., 1999). Moreover, DEP impair the regulation of vascular tone and endogenous fibrinolysis and causes prothrombotic events (Mills et al., 2005, Mills et al., 2007).

An important aspect of the epidemiological associations between air pollution and either morbidity or mortality is that the acute adverse effects appear to be most marked in people with pre-existing compromised cardiovascular function, such as hypertension (Brook et al., 2010). To give credibility for these observations, several experimental studies have been designed to test whether and to what extent the effect of particulate air pollution are aggravated using animal model of angiotensin II-induced hypertension (Nemmar et al., 2011b, Sun et al., 2008, Ying et al., 2009). Indeed, exposure particulate matter with diameter ≤2.5 μm (PM_2.5) was found to potentiate angiotensin II-induced hypertension (Sun et al., 2008, Ying et al., 2009). In addition, PM_2.5 increased angiotensin II-induced cardiac hypertrophy, collagen deposition, and cardiac and vascular RhoA activation, suggesting that cardiovascular health effects are indeed the results of air pollution exposure (Ying et al., 2009). Using the same mouse model of hypertension, we have recently demonstrated that pulmonary exposure to DEP causes thrombotic complications, and that these effects were aggravated in hypertensive mice (Nemmar et al., 2011b). However, the effects of DEP on airway resistance, lung inflammation and oxidative stress in angiotensin II-induced hypertension were not reported before.

The hypothesis tested here is whether and to what extent could exposure to DEP exacerbate pulmonary inflammation and airway resistance in hypertensive mice. Therefore, the aim of the present study is to investigate the effect of DEP on pulmonary function measured invasively using forced oscillation technique, and lung inflammation and oxidative stress assessed by bronchoalveolar lavage fluid analysis in normotensive mice, and in a specific model of hypertension, i.e. angiotensin II-induced hypertension in mice.