Morphologic Investigations of the Guinea Pig Model of Iron Overload

Abstract

We have developed a guinea pig model of iron overload toxicity. Animals were administered intraperitoneal iron dextran 3 times a week to achieve total body iron load of 0.25,0.5 1.0, 1.5, and 2.0 g Fe/kg body weight in less than 30 days. Quantitation of tissue iron levels with atomic absorption indicated increased iron deposition in liver and heart of the iron-loaded guinea pigs (p -= 0.001). Additionally, the iron-loaded pigs demonstrated decreased nuclear magnetic resonance spectropscopy T1 relaxation times in both liver and heart (p < 0.001). Serum iron, total body iron capacity, and transfenin saturation values were also determined in guinea pigs treated with 0.25,0.5, and 1.0 g Fe/kg body weight. Serum iron and total iron-binding capacity were significantly increased at 0.5 and 1.0 g Fe/kg; transfemn saturation was elevated at 0.25 and 1.0 g Fe/ kg. Histologic examination of liver, heart, and bone marrow as well as ultrastructural studies on liver and heart confirmed increased iron deposition in treated animals. At the low iron dose level of 0.5 g Fe/kg, liver iron particles were primarily confined to Kupffer cells with minimal hepatocellular localization. Increased hepatocellular iron deposition was observed with larger doses of loaded iron. Myocardial iron was most prominent in interstitial cells of the epicardium, endocardium, myocardium, and coronary adipose tissue. Ultrastructurally, the presence of iron particles in pennuclear, membrane-bound structures (consistent with lysosomes) was confirmed using x-ray microanalysis. These morphological studies suggest that in this animal model siderosis of hepatic mononuclear phagocyte and myocardial interstitial cells may be the initial lesions leading to further biochemical and functional abnormalities. Correlation between tissue iron measurements and both light and electron microscopic changes, presented in this report, serve to introduce the iron-loaded guinea pig as a model for the study of iron-induced tissue damage.

Animal Models of Heart Failure

“…In rodent models of acquired restrictive cardiomyopathy, investigators have used simple analogues of clinically detrimental exposures to produce acquired hemochromatosis [181][182][183] and radiation-induced myocardial disease 184 -186 or immune sensitization and adoptive cell transfer to produce eosinophilic myocarditis. 187 Although scleroderma (also known as systemic sclerosis) is an etiology of acquired restrictive cardiomyopathy, numerous studies used the tight skin (Tsk) mouse as a model of scleroderma before 188,189,191,192 and after 190,193 the recognition that fibrillin-1 overexpression is responsible for the excessive fibrosis associated with this strain.…”

Earliest cardiac toxicity induced by iron overload selectively inhibits electrical conduction

“…The ratio of serum iron to total iron binding capacity was also increased in the iron-loaded guinea pigs (1). Furthermore, studies with the guinea pig model confirm iron-induced lysosomal membrane fragility and increased peroxidation of membranes (30). In humans, iron-induced cardiac disease develops after years of a gradual increase in tissue iron concentration.…”

“…Evaluation of cardiac electrical conduction and ventricular contractility was performed 2 wk after the guinea pigs received their last injection (1,30). Experimental procedures and animal housing conditions were approved by the Michigan State University committee for animal experimentation.…”

“…This report uses the guinea pig model of iron overload to investigate the threshold of iron-induced delay or blockade of myocardial electrical conduction measured at the Purkinje fiber-papillary muscle (PF-PM) junction (1,30). The decrease in electrical conduction was correlated with tissue iron concentrations and iron-induced decreases in liver MR-T2.…”

Cardiac Iron Determines Cardiac T2*, T2, and T1 in the Gerbil Model of Iron Cardiomyopathy

“…Although iron dextran-loaded gerbils exhibit many of the functional and electrophysiological characteristics of human iron cardiomyopathy, [21][22][23][24] including comparable "lethal" cardiac iron levels, they exhibit significantly more interstitial iron deposition than in human disease, a typical finding in rodent models. 41,42 Changes in iron deposition at the cellular scale will influence the relative strength of T2 and T2* changes. T2* is significantly more robust to changes in intercellular and intracellular iron distribution than T2 because the proton-iron interactions responsible for T2* relaxation are longer in range than for T2 relaxation.…”