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).
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.
Growth hormone releasing hormone (GHRH) antagonists enhance endothelial barrier function and counteract the LPS‐induced lung endothelial hyperpermeability, the cardinal feature of the acute respiratory distress syndrome (ARDS). The unfolded protein response (UPR) is a multifaceted molecular mechanism, strongly involved in tissue defense against injury. The current study introduces the induction of UPR by GHRH antagonists, since those peptides induced several UPR activation markers, including the inositol‐requiring enzyme‐1α (IRE1α), the protein kinase RNA‐like ER kinase (PERK), and the activating transcription factor 6 (ATF6). On the other hand, the GHRH agonist MR‐409 exerted the opposite effects. Furthermore, GHRH antagonists counteracted the kifunensine (UPR suppressor)‐induced lung endothelial barrier dysfunction. Our observations suggest that UPR mediates, at least in part, the protective effects of GHRH antagonists in the lung microvasculature. To the best of our knowledge; this is the first study to provide experimental evidence in support of the hypothesis that UPR induction is a novel mechanism by which GHRH antagonists oppose severe human disease, including ARDS.
Inhibition of Hsp90 is associated with anti-inflammatory effects. We employed human lung microvascular endothelial cells to investigate the effects of the Hsp90 inhibitors 17-AAG, AUY-922 and 17-DMAG in the unfolded protein response (UPR) and viability of lung cells. Our observations indicate that moderate doses of those compounds trigger the activation of the UPR without inducing lethal effects
in vitro
. Indeed, AUY-922 triggered UPR activation in the lungs of C57BL/6 mice. UPR has been previously involved in the enhancement of the lung endothelial barrier function. Thus, the present study suggests that the barrier protective effects of Hsp90 inhibition in the lung microvasculature are highly probable to be associated with the activation of the UPR. Hence, the development of novel compounds which stochastically capacitate the repairing elements of UPR, may deliver new therapeutic possibilities against the severities of the acute respiratory distress syndrome.
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