Abstract
Juvenile toxicity studies have become an important and crucial focus of the preclinical drug industry. To accurately distinguish the potential detrimental effects of new drugs on the cardio‐respiratory system, it is essential to thoroughly define the normal tissue remodeling features characterizing the development and maturation of this system. The purpose of this study was to investigate the key histomorphological postnatal changes of the cardio‐respiratory system in Sprague‐Dawley rats from birth to postnatal day (PnD) 30, with a special focus on cell proliferation and apoptosis. Formalin‐fixed and paraffin‐embedded lung, trachea, heart and aorta were obtained from 51 Sprague Dawley rats divided in 13 timepoints according to age (PnD1, 2, 4, 6, 8, 10, 14, 17, 21, 24, 26, 28, and 30). Whenever possible, equal numbers of females and males were used in each group. Sections were cut at 4mm thickness and stained with hematoxylin and eosin. In addition, immunohistochemical demonstration of vimentin within lung samples and distinction between collagen and elastin fibers within the aortic wall with Masson's trichrome stain was performed. When relevant, immunohistochemistry staining was performed to highlight apoptosis (caspase‐3) and cell proliferation (Ki‐67). The ratio of heart weight relative to body weight was calculated for each timepoint and was higher at birth, then progressively decreased until PnD30. The rat heart was morphologically immature at birth and developed by cell hyperplasia over the perinatal period followed by cell hypertrophy around the third postnatal week. The newborn myocardium was hypercellular with less prominent cross‐striations, and mitotic figures and apoptotic bodies were frequently seen. The aortic wall progressively increased in thickness throughout the duration of the study as a result of an accumulation of extracellular matrix (collagen and elastic fibers). At birth, the trachea was lined by immature columnar ciliated epithelial cells, and submucosal glands became visible around one week after birth. The newborn rat had no alveoli but instead possessed large gas exchange units termed “primary saccules” characterized by highly cellular walls with a central sheet of connective tissue flanked on both sides by flattened cells (primary septa). An intense interstitial cellular proliferation was observed in the lungs between PND6 and PND14 resulting in new secondary septa, which were highly vimentin immunopositive. By the end of the third postnatal week, the septa underwent noticeable thinning and the lung parenchyma progressively matured, resulting in increased gas exchange surfaces. The findings described herein suggest that the cardio‐respiratory system of rats is immature at birth. The lungs and airways reached maturity 3 weeks after birth while cardiomyocyte hypertrophy was noticed until PnD30. The data generated will serve as background historical database that will be valuable when performing postnatal developmental toxicity studies.Support or Funding InformationMitacs
Published Version
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