Nanodomains in cardiopulmonary disorders and the impact of air pollution

Abstract

Air pollution is a major environmental threat and each year about 7 million people reported to die as a result of air pollution. Consequently, exposure to air pollution is linked to increased morbidity and mortality world-wide. Diesel automotive engines are a major source of urban air pollution in the western societies encompassing particulate matter and diesel exhaust particles (DEP). Air pollution is envisioned as primary cause for cardiovascular dysfunction, such as ischemic heart disease, cardiac dysrhythmias, heart failure, cerebrovascular disease and stroke. Air pollution also causes lung dysfunction, such as chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and specifically exacerbations of these diseases. DEP induces inflammation and reactive oxygen species production ultimately leading to mitochondrial dysfunction. DEP impair structural cell function and initiate the epithelial-to-mesenchymal transition, a process leading to dysfunction in endothelial as well as epithelial barrier, hamper tissue repair and eventually leading to fibrosis. Targeting cyclic adenosine monophosphate (cAMP) has been implicated to alleviate cardiopulmonary dysfunction, even more intriguingly cAMP seems to emerge as a potent regulator of mitochondrial metabolism. We propose that targeting of the mitochondrial cAMP nanodomain bear the therapeutic potential to diminish air pollutant - particularly DEP - induced decline in cardiopulmonary function.

Keywords: air pollution; cAMP; cardiopulmonary; diesel exhaust particles; mitochondria; nanodomains.

Figure 1.. Particulate matter — known as coarse particles — has the size less than 10 µm and has the ability to deposit in the upper respiratory tract.

Fine particles are less than 2.5 µm and are able to penetrate into the lower respiratory tract. Ultrafine particles are less than 0.1 µm and are able to penetrate into alveoli region and may even reach the vascular system [35,36]. Diesel exhaust particles (DEP) induces inflammation, oxidative stress, production of reactive oxygen species (ROS) and mitochondria dysfunction potentially leading to cardiopulmonary dysfunction. See text for further details.

Figure 2.. Cyclic AMP Nanodomains.

(A) Cyclic AMP nanodomains in inflammatory and structural cells diverse such as eosinophils, macrophages, neutrophils, lymphocytes, monocytes, epithelial cells, airway smooth muscle cells, fibroblasts, cardiomyocytes, endothelial cells and myofibroblasts. (B) Cellular effects caused by diesel exhaust particles (DEP) in inflammatory cells and structural cells. DEP induces the production of reactive oxygen species (ROS). Subsequently, ROS production induces changes in mitochondrial membrane potential leading to mitochondria dysfunction and mitochondria damage. Mitochondrial cAMP is generated from ATP by soluble adenylyl cyclase (sAC) present in the mitochondria matrix. Levels of cAMP are regulated by phosphodiesterase (PDE) degrading cAMP to 5′AMP. A-kinase anchoring protein (AKAP) 1 recruits macromolecules to mitochondria. Shown are the mitochondrial respiratory chain complexes I–V localized in the inner membrane of mitochondria. See text for further details.

Figure 2.. Cyclic AMP Nanodomains.

(A) Cyclic AMP nanodomains in inflammatory and structural cells diverse such as eosinophils, macrophages, neutrophils, lymphocytes, monocytes, epithelial cells, airway smooth muscle cells, fibroblasts, cardiomyocytes, endothelial cells and myofibroblasts. (B) Cellular effects caused by diesel exhaust particles (DEP) in inflammatory cells and structural cells. DEP induces the production of reactive oxygen species (ROS). Subsequently, ROS production induces changes in mitochondrial membrane potential leading to mitochondria dysfunction and mitochondria damage. Mitochondrial cAMP is generated from ATP by soluble adenylyl cyclase (sAC) present in the mitochondria matrix. Levels of cAMP are regulated by phosphodiesterase (PDE) degrading cAMP to 5′AMP. A-kinase anchoring protein (AKAP) 1 recruits macromolecules to mitochondria. Shown are the mitochondrial respiratory chain complexes I–V localized in the inner membrane of mitochondria. See text for further details.