The orl rat is more responsive to methacholine challenge than wild type.

BACKGROUND: This study presents an animal model of native airway hyperresponsiveness (AHR). AHR is a fundamental aspect of asthma and reflects an abnormal response characterized by airway narrowing following exposure to a wide variety of non-immunological stimuli. Undescended testis (UDT) is one of the most common male congenital anomalies. The orl rat is a Long Evans substrain with inherited UDT. Since boys born with congenital UDT are more likely to manifest asthma symptoms, the main aim of this study was to investigate the alternative hypothesis that orl rats have greater AHR to a methacholine aerosol challenge than wild type rats. METHODS: Long Evans wild type (n = 9) and orl (n = 13) rats were anesthetized, tracheostomized, and mechanically ventilated at 4 weeks of age. Escalating concentrations of inhaled methacholine were delivered. The methacholine potency and efficacy in the strains were measured. Respiratory resistance was the primary endpoint. After the final methacholine aerosol challenge, the short-acting ß2-adrenoceptor agonist albuterol was administered as an aerosol and lung/diaphragm tissues were assayed for interleukin (IL)-4, IL-6, and tumor necrosis factor (TNF)-α. Histological and histomorphometrical analyses were performed. RESULTS: The methacholine concentration-response curve in the orl group indicated increased sensitivity, hyperreactivity, and exaggerated maximal response in comparison with the wild type group, indicating that orl rats had abnormally greater AHR responses to methacholine. Histological findings in orl rats showed the presence of eosinophils, unlike wild type rats. ß2-Adrenoceptor agonist intervention resulted in up-regulation of IL-4 diaphragmatic levels and down-regulation of IL-4 and IL-6 in the lungs of orl rats. CONCLUSION: orl rats had greater AHR than wild type rats during methacholine challenge, with higher IL-4 levels in diaphragmatic tissue homogenates. Positive immunostaining for IL-4 was detected in lung and diaphragmatic tissue in both strains. This model offers advantages over other pre-clinical murine models for studying potential mechanistic links between cryptorchidism and asthma. This animal model may be useful for further testing of compounds/therapeutics options for treating AHR.

Exogenous metalloporphyrins alter the organization and function of cultured neonatal rat heart cells via modulation of heme oxygenase activity.

Heme oxygenase (HO), the enzyme responsible for heme catabolism, has been associated with the function of both skeletal and smooth muscle cells and with protection of the heart against ischemia/reperfusion injury. Exposure of skeletal muscle cultures to heme, the physiological substrate for HO, has been shown to improve differentiation and aerobic metabolism. Little is known, however, about the roles that heme and heme metabolism play in cardiac muscle, and the present study was conducted to examine the effects of exogenous heme on cultured heart cells in the presence or absence of modulators of HO activity. Treatment of neonatal rat ventricular cells with heme resulted in increases in four key indicators: (1) the activity of metabolic enzymes, (2) the rate of spontaneous contraction, (3) the level of myosin heavy chain (MyHC) expressed, and (4) the amount of actin organized as filaments. Treatment with heme while metabolically inhibiting increased HO activity altered these effects such that: (1) increases in enzyme activities were attenuated, (2) spontaneous beating ceased, (3) the level of MyHC was reduced, and (4) the amount of filamentous actin was severely decreased to the point where myofibrils were no longer evident. These results suggest that heme and its catabolites act to modulate aspects of cardiac cell function and organization.