Growth Hormone-Releasing Hormone (GHRH) regulates the release of growth hormone from the anterior pituitary gland. GHRH also acts as a growth and inflammatory factor in a variety of experimental models in oncology. In the current study, we used bovine pulmonary arterial cells in order to investigate the effects of GHRH and its antagonistic and agonistic analogs in key intracellular pathways that regulate endothelial permeability. GHRH antagonists suppressed the activation of MLC2, ERK1/2, JAK2/STAT3 pathway and increased the intracellular P53 and pAMPK levels. In contrast, both GHRH and GHRH agonist MR409 exerted the opposite effects. Furthermore, GHRH antagonists supported the integrity of endothelial barrier, while GHRH and GHRH agonists had the contrary effects, as reflected in measurements of transendothelial resistance. Our observations support the evidence for the antiinflammatory role of GHRH antagonists in the vasculature. Moreover, our results suggest that GHRH antagonists should be considered as promising therapeutic agents for treating severe respiratory abnormalities, such as the lethal Acute Respiratory Distress Syndrome (ARDS).
P53 has been recently involved in the defense against inflammation. The “guardian of the genome” appears to orchestrate cellular responses against bacterial toxins, by regulating crucial pathways that orchestrate the vascular barrier functions. Indeed, an emerging body of evidence suggests that this tumor suppressor is involved in the mediation of the beneficial effects of Hsp90 inhibition in the inflamed endothelium. Interestingly, those compounds augment the abundance of P53 in the intracellular niche, while LPS dramatically reduces it. The current study focuses on the outcome of LPS and Hsp90 inhibition on P53 phosphorylation, since this modification negatively affects P53 stability. In an in “vitro” model of LPS – induced vascular leak in bovine pulmonary arterial endothelial cells, LPS induced P53 phosphorylation in four distinct residues, namely Ser. 6, Ser. 15, Ser. 33 and Ser. 392. Furthermore, LPS triggered the activation of the myosin light chain 2, which produces endothelial barrier dysfunction by cellular retraction and intercellular gap formation. Indeed, mice exposed to the toxin demonstrated elevated levels of the pro - inflammatory cytokines IL- 2 and IL-10 in the bronchoalveolar lavage fluid. In bold contrast, the HSP90 inhibitor 17-DMAG, counteracted the LPS - induced effects both in vivo and in vitro. Specifically, this hsp90 inhibitor reduced phosphorylated P53 levels and lessened the activation of myosin light chain 2 (phosphorylation) in the bovine endothelium. Moreover, 17 - DMAG suppressed inflammation in mouse lungs, as reflected in reduced IL-2 and IL-10 BALF levels. In summary, the present results support previous observations on the protective role of P53 against inflammation and clarify mechanisms that govern vascular barrier function.
Lung endothelial barrier dysfunction leads to severe pathologies, including the lethal Acute Respiratory Distress Syndrome. P53 has been associated with anti‐inflammatory activities. The current study employs a variety of unfolded protein response (UPR) activators and inhibitors to investigate the regulation of P53 by UPR in lung cells. The bovine cells that were exposed to the UPR inductors brefeldin A, dithiothreitol, and thapsigargin; demonstrated elevated expression levels of P53 compared to the vehicle‐treated cells. On the contrary, the UPR inhibitors N‐acetyl cysteine, kifunensine, and ATP‐competitive IRE1α kinase‐inhibiting RNase attenuator; produced the opposite effects. The outcomes of the present study reveal a positive regulation between UPR and P53. Since it has been shown that a mild induction of the unfolded protein response opposes inflammation, we suggest that P53 is involved in those protective activities in the lung.
Group B streptococcus (GBS) infection is a leading cause of death among newborns in developed countries. Data on the burden of GBS in Asian countries are lacking. This study aimed to understand (i) the rate of maternal rectovaginal GBS carriage, (ii) the rate of vertical transmission of GBS, as determined by culturing ear, umbilicus, and nasal swabs, and (iii) the distribution of GBS serotypes. This prospective observational study was conducted between September 2012 and November 2013 at Kumudini Women's Medical College Hospital, a secondary-level hospital in Mirzapur, Bangladesh. The study enrolled pregnant women who visited the outpatient clinic for antenatal care (ANC) and/or delivered a child in the inpatient department of Kumudini Women's Medical College Hospital and the babies born to those mothers. 12% [20/172 isolates]). This study shows that Bangladesh has all of the ingredients for invasive GBS disease, including colonization of mothers by invasive serotypes and vertical transmission to babies.
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