Pulmonary oxidative stress, inflammation, and dysregulated iron homeostasis in rat models of cardiovascular disease.
Underlying cardiovascular disease (CVD) is a risk factor for the exacerbation of air pollution health effects. Pulmonary oxidative stress, inflammation, and altered iron (Fe) homeostasis secondary to CVD may influence mammalian susceptibility to air pollutants. Rodent models of CVD are increasingly used to examine mechanisms of variation in susceptibility. Baseline cardiac and pulmonary disease was characterized in healthy normotensive Wistar Kyoto (WKY) rats, cardiovascular compromised spontaneously hypertensive rats (SHR), and spontaneously hypertensive heart failure (SHHF) rats. Blood pressure, heart rate, and breathing frequencies were measured in rats 11 to 12 wk of age, followed by necropsy at 14 to 15 wk of age. Blood pressure and heart rate were increased in SHR and SHHF relative to WKY rats (SHR > SHHF > WKY). Increased breathing frequency in SHHF and SHR (SHR > SHHF > WKY) resulted in greater minute volume relative to WKY. Bronchoalveolar lavage fluid (BALF) protein and neutrophils were higher in SHHF and SHR relative to WKY (SHHF >> SHR > WKY). Lung ascorbate and glutathione levels were low in SHHF rats. BALF Fe-binding capacity was decreased in SHHF relative to WKY rats and was associated with increased transferrin (Trf) and ferritin. However, lung ferritin was lower and Trf was higher in SHHF relative to WKY or SHR rats. mRNA for markers of inflammation and oxidative stress (macrophage inflammatory protein [MIP]-2, interleukin [IL]-1alpha, and heme oxygenase [HO]-1) were greater in SHHF and SHR relative to WKY rats. Trf mRNA rose in SHR but not SHHF relative to WKY rats, whereas transferrin receptors 1 and 2 mRNA was lower in SHHF rats. Four of 12 WKY rats exhibited cardiac hypertrophy despite normal blood pressure, while demonstrating some of the pulmonary complications noted earlier. This study demonstrates that SHHF rats display greater underlying pulmonary complications such as oxidative stress, inflammation, and impaired Fe homeostasis than WKY or SHR rats, which may play a role in SHHF rats' increased susceptibility to air pollution.
Shannahan
Jonathan H
JH
Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina, USA. Shannahan.jonathan@epa.gov
Schladweiler
Mette C J
MC
Richards
Judy H
JH
Ledbetter
Allen D
AD
Ghio
Andrew J
AJ
Kodavanti
Urmila P
UP
D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics; D006706:Homeostasis / Q000502:physiology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009765:Obesity; D018384:Oxidative Stress; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012129:Respiratory Function Tests; D020521:Stroke; D014168:Transferrin / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D014168:Transferrin; D005293:Ferritins; D007501:Iron; D005978:Glutathione; D001205:Ascorbic Acid