Journalartikel
Autorenliste: Czikora, Istvan; Sridhar, Supriya; Gorshkov, Boris; Alieva, Irina B.; Kasa, Anita; Gonzales, Joyce; Potapenko, Olena; Umapathy, Nagavedi S.; Pillich, Helena; Rick, Ferenc G.; Block, Norman L.; Verin, Alexander D.; Chakraborty, Trinad; Matthay, Michael A.; Schally, Andrew V.; Lucas, Rudolf
Jahr der Veröffentlichung: 2014
Zeitschrift: Frontiers in Physiology
Bandnummer: 5
ISSN: 1664-042X
Open Access Status: Gold
DOI Link: https://doi.org/10.3389/fphys.2014.00259
Verlag: Frontiers Media
Rationale: Antibiotic treatment of patients infected with G(-) or G(+) bacteria promotes release of the toxins lipopolysaccharide (LPS) and pneumolysin (PLY) in their lungs. Growth Hormone-releasing Hormone (GHRH) agonist JI-34 protects human lung microvascular endothelial cells (HL-MVEC), expressing splice variant 1 (SV-1) of the receptor, from PLY-induced barrier dysfunction. We investigated whether JI-34 also blunts LPS-induced hyperpermeability. Since GHRH receptor (GHRH-R) signaling can potentially stimulate both cAMP-dependent barrier-protective pathways as well as barrier-disruptive protein kinase C pathways, we studied their interaction in G H RH agonist-treated HLMVEC, in the presence of PLY by means of siRNA-mediated protein kinase A (PKA) depletion. Methods: Barrier function measurements were done in HLMVEC monolayers using Electrical Cell substrate Impedance Sensing (ECIS) and VE-cadherin expression by Western blotting. Capillary leak was assessed by Evans Blue dye (EBD) incorporation. Cytokine generation in broncho-alveolar lavage fluid (BALE) was measured by multiplex analysis. PKA and PKC-alpha activity were assessed by Western blotting. Results: GHRH agonist JI-34 significantly blunts LPS-induced barrier dysfunction, at least in part by preserving VE-cadherin expression, while not affecting inflammation. In addition to activating PKA, GHRH agonist also increases PKC-alpha activity in PLY-treated HLMVEC. Treatment with PLY significantly decreases resistance in control siRNA-treated HLMVEC, but does so even more in PKA-depleted monolayers. Pretreatment with GHRH agonist blunts PLY-induced permeability in control siRNA-treated HLMVEC, but fails to improve barrier function in PKA-depleted PLY-treated monolayers. Conclusions: GHRH signaling in HLMVEC protects from both LPS and PLY-mediated endothelial barrier dysfunction and concurrently induces a barrier-protective PKA-mediated and a barrier-disruptive PKC-alpha-induced pathway in the presence of PLY, the former of which dominates the latter.
Abstract:
Zitierstile
Harvard-Zitierstil: Czikora, I., Sridhar, S., Gorshkov, B., Alieva, I., Kasa, A., Gonzales, J., et al. (2014) Protective effect of Growth Hormone-Releasing Hormone agonist in bacterial toxin-induced pulmonary barrier dysfunction, Frontiers in Physiology, 5, Article 259. https://doi.org/10.3389/fphys.2014.00259
APA-Zitierstil: Czikora, I., Sridhar, S., Gorshkov, B., Alieva, I., Kasa, A., Gonzales, J., Potapenko, O., Umapathy, N., Pillich, H., Rick, F., Block, N., Verin, A., Chakraborty, T., Matthay, M., Schally, A., & Lucas, R. (2014). Protective effect of Growth Hormone-Releasing Hormone agonist in bacterial toxin-induced pulmonary barrier dysfunction. Frontiers in Physiology. 5, Article 259. https://doi.org/10.3389/fphys.2014.00259
Schlagwörter
Cadherin; capillary leak; CYCLASE-ACTIVATING POLYPEPTIDE; growth hormone-releasing hormone; INDUCED LUNG INJURY; PKA; PNEUMOLYSIN; protein kinase C
