Substance P protects against hyperoxic-induced lung injury in neonatal rats

Abstract

The aim of the study was to investigate the effects of substance P (SP) in hyperoxia-induced lung injury in newborn rats. Thirty-two rat pups were randomly divided into four groups: normoxia/saline, normoxia/SP, hyperoxia/saline and hyperoxia/SP. In a separate set of experiments, the neonatal rat pups were exposed to 21% or >95% O2 for 14 days with or without intraperitoneal administration of SP. On day 14, the animals were sacrificed and the lungs were processed for histology and biochemical analysis. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used for the detection of apoptosis. Antioxidant capacity was assessed by glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), oxidative stress was assessed by determining the extent of formation of malondialdehyde (MDA), activities of NADPH oxidase activity, and formation of reactive oxygen species (ROS). The activity of phospho-p38 (p-p38) and -ERK1/2 (p-ERK1/2) proteins and expression of NF-E2-related factor 2 (NRF2) were detected by Western blot, and the expression of p-p38 was detected by immunofluorescence analysis. Compared with the hyperoxia treatment, the lung damage was significantly ameliorated following the SP treatment. Furthermore, the lungs from the pups exposed to hyperoxia TUNEL-positive nuclei increased markedly and decreased significantly after SP treatment. The levels of MDA decreased and that of GSH-Px and SOD increased following the SP treatment. The SP treatment significantly suppressed the activity of NADPH oxidase and reduced ROS production. SP stimulation may result in blocking p38 MAPK and ERK signaling pathways, and the activities of p-p38 and p-ERK, and expression of NRF2 decreased following the SP treatment. These findings indicate that SP can ameliorate hyperoxic lung injury through decreasing cell apoptosis, elevating antioxidant activities, and attenuating oxidative stress.

The expression of miR‐125b in Nrf2‐silenced A549 cells exposed to hyperoxia and its relationship with apoptosis

“…15 Therefore, enhancing the antioxidation ability and reducing ROS production are key to reducing the incidence of BPD and are important for improving the survival rate and quality of life of premature infants. 16 The periods of lung development include the embryonic, pseudoglandular, canalicular, saccular and alveolar periods. At present, the animal models of BPD are mainly generated by hyperoxia exposure, and rodents are the most widely used model.…”

Molecular mechanisms underlying hyperoxia acute lung injury

“…These researchers also demonstrated that cell cultures on laminin substrates, with respect to other plastic supports, resulted in increased phosphorylation of ERK 1/2 [56]. Huan et al have shown that the addition of SP to cell cultures promotes proliferation and inhibits apoptosis by suppressing JNK and p38 signaling pathways after hyperoxia exposure, which attenuates oxidative lung injury [57,58]. Other researchers reported ERK 1/2, JNK and p38 significant increase under prolonged exposure to hyperoxic conditions [59,60].…”

“…This may prove helpful in developing future therapies for ALI based on PKCd chemical inhibitors [62]. Simultaneously, Otterbein et al reported [51] 2004 ATP ERK 1/2 phosphorylation [31] 2004 DPI NOX inhibition [52] 2005 Inosine ERK 1/2 phosphorylation [56] 2006 RA ERK 1/2 phosphorylation JNK and p38 inhibition [54] 2009 SP JNK and p38 inhibition [57] 2010 Trx JNK and p38 inhibition [1] 2011 Enoxaparin PAI-1 and HMGB-1 inhibition [59] 2012 rottlerin PKCd inhibition [42] 2012 H 2 and HS Caspase 3/9 and NfkB inhibition [58] 2012 miR-16 TGFb1 inhibition [9] 2014 Anti-HMGB-1 and EP HMGB-1 inhibition [60] 2015 CO p38 inhibition the protective role of low CO concentration in hyperoxic lung injury, its extended survival and its potent anti-inflammatory effects with reduced inflammatory cell influx into the lungs and marked attenuation of pro-inflammatory cytokines' expression [63]. Indeed, exogenous administration of CO limits the progress of histopathological changes and attenuates cytokine expression induced by hyperoxia [32,63].…”

Oxidative stress diseases unique to the perinatal period: A window into the developing innate immune response

“…Hyperoxia-induced ERK signaling occurs in both neonatal and adult rodents. 55, 59–63 Some have demonstrated that hyperoxia-induced ERK signaling does not occur in neonatal lung, 64 and only occurs in the adult lung with the addition of mechanical ventilation. 65 The effect of ERK blockade on hyperoxia-induced lung injury has been inconsistent, 59, 60 but appears to benefit the adult.…”

“…55, 59–63 Some have demonstrated that hyperoxia-induced ERK signaling does not occur in neonatal lung, 64 and only occurs in the adult lung with the addition of mechanical ventilation. 65 The effect of ERK blockade on hyperoxia-induced lung injury has been inconsistent, 59, 60 but appears to benefit the adult. 55 Taken together, we can conclude that hyperoxia-induced ERK activation is developmentally regulated, and conclusions drawn from these and future investigations must be placed in the correct context.…”