protective effect of growth hormone-releasing hormone agonist in bacterial toxin-induced pulmonary barrier dysfunction.
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ID: 131856
2014
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Abstract
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 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 signaling can potentially stimulate both cAMP-dependent barrier-protective pathways as well as barrier-disruptive protein kinase C pathways, we studied their interaction in GHRH agonist-treated HL-MVEC, in the presence of PLY, by means of siRNA-mediated PKA depletion.Methods. Barrier function measurements were done in HL-MVEC monolayers using Electrical Cell substrate Impedance Sensing (ECIS) and VE-cadherin expression by Western blotting. Capillary leak was assessed by Evans Blue dye incorporation. Cytokine generation in broncho-alveolar lavage fluid 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 HL-MVEC. Treatment with PLY significantly decreases resistance in control siRNA-treated HL-MVEC, but does so even more in PKA-depleted monolayers. Pretreatment with GHRH agonist blunts PLY-induced permeability in control siRNA-treated HL-MVEC, but fails to improve barrier function in PKA-depleted PLY-treated monolayers. Conclusions. GHRH signaling in HL-MVEC 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.
| Reference Key |
eczikora2014frontiersprotective
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| Authors | ;Istvan eCzikora;Supriya eSridhar;Boris eGorshkov;Anita eKasa;Irina eAlieva;Irina eAlieva;Joyce eGonzales;Olena ePotapenko;Nagavedi Siddaramappa Umapathy;Alexander D Verin;Helena ePillich;Ferenc G Rick;Ferenc G Rick;Norman L Block;Norman L Block;Trinad eChakraborty;Michael A Matthay;Andrew V Schally;Andrew V Schally;Rudolf eLucas;Rudolf eLucas;Rudolf eLucas |
| Journal | Journal of clinical and experimental dentistry |
| Year | 2014 |
| DOI |
10.3389/fphys.2014.00259
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| URL | |
| Keywords |
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