Maternal Deprivation Decelerates Postnatal Morphological Lung Development of F344 Rats

Abstract

Intensive medical care at premature born infants is often associated with separation of neonates from their mothers. Here, early artificial prolonged separation of rat pups from their dams (Maternal Deprivation, MD) was used to study potential impact on morphological lung maturation. Furthermore, we investigated the influence of an endogenous deficiency of the neuropeptide-cleaving dipeptidyl peptidase IV (DPP4), since the effects of MD are known to be partly mediated via neuropeptidergic effects, hypothesizing that MD will lead to a retardation of postnatal lung development, DPP4-dependendly. We used wild type and CD26/DPP4 deficient rats. For MD, the dam was placed each day into a separate cage for 2 h, while the pups remained in the nest on their own. Morphological lung maturation and cell proliferation at the postnatal days 7, 10, 14, and 21 were determined morphometrically. Maternally deprived wild types showed a retarded postnatal lung development compared with untreated controls in both substrains. During alveolarization, an increased thickness of alveolar septa and a decreased surface of septa about 50% were found. At the end of the morphological lung maturation, the surface of the alveolar septa was decreased at about 25% and the septal thickness remained increased about 20%. The proliferation rate was also decreased about 50% on day 14. However, the MD induced effects were less pronounced in DPP4-deficient rats, due to a significant deceleration already induced by DPP4-deficiency. Thus, MD as a model for postnatal stress experience influences remarkably postnatal development of rats, which is significantly modulated by the DPP4-system. Anat Rec, 297:317-326, 2014. V C 2013 Wiley Periodicals, Inc.

Recent advances in the mechanisms of lung alveolarization and the pathogenesis of bronchopulmonary dysplasia

“…This concept of fetal priming has also been observed in the rodent hyperoxia model using maternal diabetes as a first hit, in which streptozotocin-induced diabetes in rats before pregnancy appeared to modulate the effects of hyperoxia on septal wall thickness in pup lungs, although the precise implications of this are not clear (173). In terms of other new models, the observation that maternal deprivation (that is, separation of mother and pups) in rats also led to a pronounced blunting of lung development (assessed by MLI), ostensibly mediated by dipeptidyl peptidase IV, suggests that maternal deprivation may represent a new (stress-induced) rat model of BPD (150). This idea possibly intersects with the recent observation that maternal stress during pregnancy alters the predisposition of pups to allergy susceptibility, in which a role for glucocorticoids was implicated (193).…”

Lung development and immune status under chronic LPS exposure in rat pups with and without CD26/DPP4 deficiency

“…Sectioning of each lung block was carried out using a Cryostat (Leica CM 3050S, München, Germany). After staining with hematoxylin-eosin, scanning of test fields was carried out on a Nikon Eclipse 80i microscope (Tokyo, Japan) connected to a digital camera using the Stereo Investigator Version 6 software (Micro Bright Field, Vermont, USA) as described before (Hupa et al 2014). According to the guidelines for standardized quantitative Assessment of Lung Structure (Hsia et al 2010), the following parameters were determined using the point and intersection counting as described before (Hupa et al 2014;Schmiedl et al 2017;Wagener et al 2020):…”

“…To determine morphological lung maturation, we therefore used single-section parameters which characterize predominantly the parenchymal compartments. Using the point and intersection counting method together with the known lung volume, the determined parameters give sufficient information about the total amount of airspace and septa as well as the total septal surface area (Ochs 2014;Schmiedl et al 2017;Wagener et al 2020;Hupa et al 2014). The increase of septal surface is an indirect indication for new secondary septa and therefore of alveolarization.…”

“…After bulk alveolarization combined with vascular maturation lasted up to dpp 21, continued alveolarization occurred until adulthood (Schittny 2017 ). We have already shown that CD26 deficiency delayed the postnatal lung development (Hupa et al 2014 ; Wagener et al 2020 ) and that high doses of postnatal LPS inhalation (100 µg/2 mL NaCl) given for 10 min 1 day before and 1 day after the onset of alveolarization produced an acute but weakly pronounced inflammation and a delay in morphological lung development with a reduced morphological recovery after the end of LPS exposure in dependence of CD26 deficiency (Wagener et al 2020 ). While this procedure resembles an acute injury, the repetitive administration of LPS over 1 week used in the present is more comparable with a chronic inflammatory disorder (Wang et al 2009 ), which is a possible precondition to develop bronchopulmonary dysplasia (BPD) (Baker and Alvira 2014 ).…”

Review: innovation through research in the North American pork industry

“…Epidemiological studies in humans and early life stress models in rodent (e.g. neonatal maternal separation stress) show a link between early life stress/adversity and long-term development of lung immunology, function and respiratory disease risk later in life (Bhan et al, 2014;Hupa et al, 2014;Lee et al, 2017).…”