<p>IHC staining for CD39 (top; diffuse brown stain) and Ccr2 (bottom; punctate stain) in crocidolite-induced and chrysotile-induced MMs from <i>Bap1<sup>+/−</sup></i> mice. Arrows indicate examples of cells positively stained for Ccr2.</p>
<p>H&E images of liver fibrosis in Bap1+/- mice chronically injected i.p. with asbestos. A) Interlobular liver fibrosis in a chrysotile-exposed mouse. B) Liver fibrosis in between liver and spleen in chrysotile-injected mouse. C) Fibrosis on surface of liver in a crocidolite-exposed mouse. D) Fibrosis between liver and pancreas of a crocidolite-exposed mouse. All original images are at 200X magnification. Abbreviations: F, fibrosis; L, liver; M, mesothelioma; S, spleen; P, pancreas.</p>
<p>MM formation induced by crocidolite or chrysotile asbestos in mice with germline <i>Bap1</i> heterozygous mutation. MM formation induced by minimal exposure to crocidolite (<b>A</b> and <b>B</b>). <b>A,</b><i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> (WT) littermates injected with a total of 0.8 mg of crocidolite fibers. Left, Kaplan–Meier curves depicting survivals in <i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> groups. Right, Summary of MM incidence and median survival times. <b>B,</b> Results for <i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> mice injected with a total of 0.1 mg of crocidolite. Left, Kaplan–Meier curves. Right, Summary of MM incidence and median survival times. MM formation induced by high (<b>C</b>) and minimal (<b>D</b>) exposure to chrysotile. <b>C,</b><i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> mice were injected with a total of 3.2 mg of chrysotile. Left, Kaplan–Meier survival curves. Right, MM incidence and median survival times. <b>D,</b><i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> mice injected with a total of 0.4 mg/mouse of crocidolite. Left, Kaplan–Meier curves. Right, MM incidence and median survival times. For all Kaplan–Meier survival curves, deaths due to all causes are included. Some mice (especially WT animals) succumbed because of adhesion-related intestinal obstructions and/or liver fibrosis.</p>
<p>MM formation induced by crocidolite or chrysotile asbestos in mice with germline <i>Bap1</i> heterozygous mutation. MM formation induced by minimal exposure to crocidolite (<b>A</b> and <b>B</b>). <b>A,</b><i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> (WT) littermates injected with a total of 0.8 mg of crocidolite fibers. Left, Kaplan–Meier curves depicting survivals in <i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> groups. Right, Summary of MM incidence and median survival times. <b>B,</b> Results for <i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> mice injected with a total of 0.1 mg of crocidolite. Left, Kaplan–Meier curves. Right, Summary of MM incidence and median survival times. MM formation induced by high (<b>C</b>) and minimal (<b>D</b>) exposure to chrysotile. <b>C,</b><i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> mice were injected with a total of 3.2 mg of chrysotile. Left, Kaplan–Meier survival curves. Right, MM incidence and median survival times. <b>D,</b><i>Bap1<sup>+/−</sup></i> and <i>Bap1<sup>+/+</sup></i> mice injected with a total of 0.4 mg/mouse of crocidolite. Left, Kaplan–Meier curves. Right, MM incidence and median survival times. For all Kaplan–Meier survival curves, deaths due to all causes are included. Some mice (especially WT animals) succumbed because of adhesion-related intestinal obstructions and/or liver fibrosis.</p>
<p>Anatomical image of peritoneal MMs (white long arrows) induced by chronic intraperitoneal injections of chrysotile in a Bap1+/- mouse. MMs developing in Bap1+/- and Bap1+/+ (wild type) littermates injected with either chrysotile or crocidolite generally were diffuse peritoneal lesions sometimes accompanied by ascites. Note that the MMs shown in this animal are unusually large for illustrative purposes. Most tumors in this model were solitary, much smaller, and diffuse. Irregular liver surface (yellow rectangle) is likely indicative of fibrosis. L, liver; LI, large intestine; M, mesothelioma.</p>
Premenopausal women have a significant reduction in coronary artery disease compared to age matched males. Little is known about the mechanism underlying this cardio protective effect of estrogen. Contradictory evidence has been published and our lack of basic understanding of hormone interactions and bioavailability of different estrogens prevents definitive interpretation of these data. We demonstrate gender-specific effects in the proliferation of coronary artery vascular smooth muscle cells obtained from a sexually mature animal model. Vascular smooth muscle cells are an integral component of the atherosclerotic plaque, and inhibition of cell proliferation by estrogen may be one mechanism by which estrogen exerts its cardio protective effect. Various types of estrogen may also have different mechanistic actions on the vascular system. No differences are demonstrated in overall estradiol binding in vascular smooth muscle cells obtained from male or female animals; however, differences in c-jun, c-fos and TIEG gene expression were gender related. Inhibition of vascular smooth muscle cell proliferation may have important implications in the prevention of atherosclerotic disease and these studies may provide evidence for the cardio protective effect of estrogen.
