Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina, USA.
J Toxicol Environ Health A. 2010;73(10):641-56. doi: 10.1080/15287390903578208.
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.
潜在的心血管疾病 (CVD) 是加剧空气污染对健康影响的一个风险因素。CVD 引起的肺部氧化应激、炎症和铁 (Fe) 稳态改变可能会影响哺乳动物对空气污染物的易感性。CVD 的啮齿动物模型越来越多地被用于研究易感性变化的机制。本研究在健康的正常血压 Wistar Kyoto (WKY) 大鼠、心血管受损的自发性高血压大鼠 (SHR) 和自发性高血压心力衰竭大鼠 (SHHF) 中描述了基础的心脏和肺部疾病。在 11 至 12 周龄的大鼠中测量血压、心率和呼吸频率，然后在 14 至 15 周龄时进行尸检。与 WKY 大鼠相比，SHR 和 SHHF 大鼠的血压和心率升高（SHR>SHHF>WKY）。SHHF 和 SHR 大鼠的呼吸频率增加（SHR>SHHF>WKY）导致每分钟通气量相对于 WKY 大鼠增加。与 WKY 大鼠相比，SHHF 和 SHR 大鼠的支气管肺泡灌洗液 (BALF) 蛋白和中性粒细胞更高（SHHF>>SHR>WKY）。SHHF 大鼠的肺抗坏血酸和谷胱甘肽水平较低。与 WKY 大鼠相比，SHHF 大鼠的 BALF Fe 结合能力降低，同时转铁蛋白 (Trf) 和铁蛋白增加。然而，与 WKY 或 SHR 大鼠相比，SHHF 大鼠的肺铁蛋白较低，Trf 较高。与 WKY 大鼠相比，SHHF 和 SHR 大鼠的炎症和氧化应激标志物（巨噬细胞炎症蛋白 [MIP]-2、白细胞介素 [IL]-1alpha 和血红素加氧酶 [HO]-1）的 mRNA 水平更高。与 WKY 大鼠相比，SHR 大鼠的 Trf mRNA 升高，但 SHHF 大鼠的 Trf mRNA 没有升高，而 SHHF 大鼠的转铁蛋白受体 1 和 2 mRNA 水平降低。尽管血压正常，但 12 只 WKY 大鼠中有 4 只出现心脏肥大，同时表现出前面提到的一些肺部并发症。本研究表明，与 WKY 或 SHR 大鼠相比，SHHF 大鼠表现出更大的潜在肺部并发症，如氧化应激、炎症和铁稳态受损，这可能在 SHHF 大鼠对空气污染的易感性增加中发挥作用。
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