Respiratory Physiology

The Cardiopulmonary Physiology Research Laboratory (CPRL) currently is conducting several projects related to the cardiovascular health effects of air pollutants.  Dr. Amie Lund is currently examining the molecular basis for air pollution-induced upregulation of vascular matrix metalloproteinases (MMP), enzymes with a crucial role in the development and eventual destabilization/erosion of atherosclerotic plaques.

Using an atherosclerosis-prone mouse model (the Apolipoprotein-deficient mouse), she has identified a role for endothelin-1, via the upregulation of NADPH oxidase and resultant generation of reactive oxygen species, in causing the transcriptional responses of MMP-9.  She is currently involved in studies to understand the cause of activation of existing extracellular MMPs by inhalation of pollutants, as well as identifying translatable serum biomarkers for human studies.

Figure 1.  Complex emissions contain compounds that can directly access the circulation and vasculature.  Our findings suggest that MMPs, while not the only factor involved in air pollution-induced vascular disease, may have a crucial role in both acute and chronic cardiovascular health effects.

 

Dr. Matthew Campen, along with collaborators at the University of New Mexico (Dr. Nancy Kanagy and Tom Cherng), is interested in the acutely-induced endothelial dysfunction that occurs following a single exposure to diesel emissions.  The mechanism appears to involve the uncoupling of nitric oxide synthase (NOS), which reduces the bioavailable nitric oxide and reduces dilatory responses to endogenous vasoactive mediators, such as acetylcholine. 

 

We have also shown that enhanced constriction to endothelin-1 depends on an NOS-dependent homeostatic feedback mechanism to temper this potent vasoconstrictive pathway.  This effect is consistent in a variety of vascular beds, including the coronary, mesenteric arterial, and mesenteric venous circulations.  The resultant endothelial dysfunction may play an important role in exacerbating pathologies related to insufficient organ perfusion, such as myocardial infarction or stroke.

 

As a core contributor to the National Environmental Respiratory Center, we have been interested in the causal components of air pollution for over a decade, investigating the relative impacts of whole exhausts (Diesel, Gasoline engines, Coal, Woodsmoke)

 

Dr. Campen further conducts studies of the individual components of the pollutant, such as, particulate matter, oxides of nitrogen , and carbon monoxide

 

These studies intertwine with the research of the various investigaotrs, in that the basic research provides sensitive and meaningful biomarkers for comparisons between atmospheres.  MMP-9 mRNA, for instance, appears sensitive to pollutant atmospheres that are high in oxides of nitrogen and carbon monoxide (e.g., gasoline emissions), but insensitive to sulfate-heavy atmospheres (e.g., coal emissions).  Dr. Campen is also interested in translating research to both whole-body outcomes, such as changes in hemodynamics, ECG, or ventilations, and human biomarkers.

Figure 2. Gasoline emissions induce a concentration-dependent change in various aortic transcriptional markers, including MMPs, endothelin (ET-1), and heme oxygenase (HO-1).  Ongoing studies are investigating the impact of contrasting pollutant atmospheres, such as coal and diesel emissions.   Beyond the focus on environmental health, the CPRL group has experience with several animal models of cardiopulmonary disease, including:   Pulmonary hypertension Systemic hypertension Right- and left-sided heart failure Atherosclerosis Hypoventilation COPD Asthma Sleep apnea   These research models are useful tools in testing the efficacy of potential therapeutics as well as elucidating the susceptibility to certain traits/diseases that may lead to the toxicity of inhaled substances.