Calcitonin Gene-Related Peptide Ameliorates Hyperoxia-Induced Lung Injury in Neonatal Rats

Abstract

Therapies with prolonged exposure to high-concentration oxygen are common in the treatment of critical pulmonary and cardiac conditions in newborns. However, prolonged exposure to hyperoxia could result in lung damages and developmental disorders manifested as acute lung injury and bronchopulmonary dysplasia, respectively. Calcitonin gene-related peptide (CGRP) has been shown to have a broad regulatory effect on the respiratory system. In this study, we explored the protective effects of CGRP on the hyperoxia-induced lung damage. Newborn Sprague-Dawley rats were randomly divided into three groups: normoxia, hyperoxia, and hyperoxia with CGRP. Hyperoxia groups were exposed to 95% oxygen for 14 days and treated once every other day with saline or CGRP. Hyperoxia exposure reduced the survival rate to 73%, when compared with the 93% survival rate observed in the normoxia group. The survival rate was improved to 84% with CGRP treatment. Treatment with CGRP under hyperoxia significantly alleviated the hyperoxia-induced lung histomorphological changes and the increases in leukocyte counts and total protein levels in bronchoalveolar lavage fluid that reflect the pulmonary microvasular damages. CGRP treatment also restored the decreased activity of superoxide dismutase, while it decreased the increased level of malondialdehyde in the lung tissues. Importantly, CGRP treatment significantly decreased the magnitude of the hyperoxia-mediated increase in the expression levels of tumor necrosis factor-α mRNA and transforming growth factor-β 1 protein. In conclusion, the hyperoxia-induced acute lung injury is associated with both oxidative stress and inflammatory responses, and CGRP may ameliorate the hyperoxia-induced lung injury by down-regulating these processes.

Regulation of the angiotensin II-p22phox-reactive oxygen species signaling pathway, apoptosis and 8-oxoguanine-DNA glycosylase 1 retrieval in hyperoxia-induced lung injury and fibrosis in rats

“…In rats, alveolar development occurs only in the uesicae stage at birth, which corresponds to 25–35 gestational weeks in humans (1). Thus, continuous hyperoxic exposure of newborn rats might induce features such as alveolar maldevelopment and fibrosis, which are similar to those of ALI in human newborns (13,14,16). In the present study, the untreated hyperoxic model group exhibited the typical intolerance to lack of oxygen on day 7, which manifested mainly as breathing difficulties following deoxygenation, cyanosis and convulsions.…”

“…Following hyperoxic exposure, H&E staining and electron microscopy experiments indicated the presence of lung injury and fibrosis, suggesting that the rat hyperoxia model was successfully established. This model is essential for the study of neonatal hyperoxia (13,14,16). …”

“…The integrated ODs of the bands were analyzed using ImageMaster software (v1.0.3.7) with the Bio-Rad Gel Doc1000 imaging system (Bio-Rad Laboratories, Inc., Hercules, CA, USA). The imaging system was used to acquire images of the X-ray films and the analysis software was used to analyze and calculate the integrated ODs (13,16). …”

Postnatal inflammation in the pathogenesis of bronchopulmonary dysplasia

“…In hyperoxia‐exposed neonatal rats, a variety of agents have been used as therapeutic agents to ameliorate hyperoxia‐induced lung inflammation/injury and/or the BPD phenotype. These include keratinocyte growth factor (KGF) (Frank, ; Franco‐Montoya et al, ), VEGF (Kunig et al, ; Thebaud et al, ; Kunig et al, ), iNO (ter Horst et al, ), inhaled ethyl nitrite (Auten et al, ), sildenafil (Ladha et al, ; Park et al, ), L‐citrulline (Vadivel et al, ), leukotriene inhibition (Funk et al, ), azithromycin (Ballard et al, ), apelin—a potent vasodilator and angiogenic factor (Visser et al, ), phosphodiesterase‐4 (PDE‐4) inhibition (de Visser et al, ; de Visser et al, ), curcumin (Sakurai et al, ), colchicine (Ozdemir et al, ), pentoxifylline (Almario et al, ), Nigella sativa oil (Tayman et al, ), calcitonin‐gene related peptide (Dang et al, ), caffeine (Weichelt et al, ), inhibition of Wnt‐signaling (Alapati et al, ; Hummler et al, ), and administration of cytidine 5′‐diphosphocholine (Cetinkaya et al, ). A variety of stem cells delivered to hyperoxia‐exposed neonatal rat lungs have improved alveolar and vascular growth (van Haaften et al, ; Zhang et al, ; Baker et al, ; Pierro et al, ).…”

Action and Protection Mechanisms of Free Radicals

“…The balance between the oxidative actions of free radicals and the level of antioxidants in a body essential for life and characterises the capacity of resistance and adaptation of a living body. Organisms are protected by the aggression of ROS in several ways: cell compartmentation, protection by antioxidant compounds and by enzymatic systems, the organisms' capacity of developing inducible adaptive responses under conditions of oxidative stress [9]. Table 1 shows that enzymatic systems are more efficient in favouring and controlling peroxidation.…”