Immediate and late systemic and lung effects of inhaled paraquat in rats

As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder in which excessive deposition of extracellular matrix leads to irreversible scarring of interstitial lung tissue. The etiology of IPF remains unknown, but growing evidence suggests that disequilibrium in oxidant/antioxidant balance contributes significantly. IPF is currently regarded as a fibroproliferative disorder triggered by repeated alveolar epithelial cell injury. Oxidative stress plays a role in many processes involved in alveolar epithelial cell injury and fibrogenesis. Here we review the role of oxidative stress in IPF, and other forms of pulmonary fibrosis, with particular attention to antioxidant defenses regulated by the redox-sensitive transcription factor nuclear factor, erythroid derived 2, like (Nrf2). Nrf2 binds specific antioxidant response elements (AREs) in the promoter of antioxidant enzyme and defense protein genes and regulates their expression in many tissue types. Nrf2 protects from several phenotypes in which enhanced oxidative burden contributes to disease pathogenesis, including cancer, acute lung injury, and pulmonary fibrosis. We suggest that promoter polymorphisms in human NRF2 may contribute to IPF susceptibility, although this hypothesis has not been tested. Pulmonary fibrosis is a highly complex disease and involves multiple genes and processes, and new therapies for cellular and molecular targets involved in pathogenic mechanisms are needed.