Regulation of angiopoietin-2 secretion from human pulmonary microvascular endothelial cells
(2016) In Lung 42(7). p.335-345- Abstract
INTRODUCTION: Sepsis is characterized by dysregulated systemic inflammation and cytokine storm. Angiopoietin-2 (Ang-2) is known to closely correlate with severity of sepsis-related acute lung injury and mortality. The aim of this study was to clarify the mechanisms involved in Ang-2 secretion to better understand the pathophysiology of sepsis.
MATERIALS AND METHODS: The concentration of Ang-2 was assessed in culture medium of pulmonary microvascular endothelial cells in the presence or absence of Gram-positive bacteria cell wall components [lipoteichoic acid (LTA) and peptidoglycan (PGN)] stimulation at different time points ranging from 15 minutes to 24 hours. Constitutive and LTA-PGN-stimulated Ang-2 level changes were also... (More)
INTRODUCTION: Sepsis is characterized by dysregulated systemic inflammation and cytokine storm. Angiopoietin-2 (Ang-2) is known to closely correlate with severity of sepsis-related acute lung injury and mortality. The aim of this study was to clarify the mechanisms involved in Ang-2 secretion to better understand the pathophysiology of sepsis.
MATERIALS AND METHODS: The concentration of Ang-2 was assessed in culture medium of pulmonary microvascular endothelial cells in the presence or absence of Gram-positive bacteria cell wall components [lipoteichoic acid (LTA) and peptidoglycan (PGN)] stimulation at different time points ranging from 15 minutes to 24 hours. Constitutive and LTA-PGN-stimulated Ang-2 level changes were also assessed after cells were pretreated with different pathway inhibitors for 1 hour.
RESULTS: Two distinctive mechanisms of Ang-2 secretion, constitutive and stimulated secretion, were identified. Constitutive secretion resulted in slow but continuous increase in Ang-2 in culture medium over time. It was regulated by 3'5'-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-Ca(2+) and nitric oxide (NO)-3'5'-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)-Ca(2+) pathways and partially regulated by N-ethyl-maleimide-sensitive factor-Ca(2+) pathways. LTA-PGN stimulation caused rapid and potent increase followed by gradual decrease of Ang-2. It was partially regulated by both Ral A-phospholipase D and NSF-Ca(2+) pathways.
CONCLUSIONS: We demonstrated characteristics and involved pathways for two distinctive secretory mechanisms, constitutive and stimulated, of Ang-2 in pulmonary microvascular endothelial cells. Considering the close correlation of Ang-2 with sepsis outcomes, our findings provide a better understanding of an important mechanism associated with sepsis pathophysiology and identify possible therapeutic targets to improve outcomes in the potentially lethal disease.
(Less)
- author
- Lee, Ji Young ; Linge, Helena M LU ; Ochani, Kanta ; Lin, Ke and Miller, Edmund J
- publishing date
- 2016-09-01
- type
- Contribution to journal
- publication status
- published
- in
- Lung
- volume
- 42
- issue
- 7
- pages
- 12 pages
- publisher
- Springer
- external identifiers
-
- scopus:84984669456
- pmid:27585839
- ISSN
- 1432-1750
- DOI
- 10.1080/01902148.2016.1218977
- language
- English
- LU publication?
- no
- id
- c4e5a46b-a5ef-42ab-b6e2-0ce20f9704ba
- date added to LUP
- 2016-10-20 11:57:39
- date last changed
- 2024-01-04 14:41:22
@article{c4e5a46b-a5ef-42ab-b6e2-0ce20f9704ba,
abstract = {{<p>INTRODUCTION: Sepsis is characterized by dysregulated systemic inflammation and cytokine storm. Angiopoietin-2 (Ang-2) is known to closely correlate with severity of sepsis-related acute lung injury and mortality. The aim of this study was to clarify the mechanisms involved in Ang-2 secretion to better understand the pathophysiology of sepsis.</p><p>MATERIALS AND METHODS: The concentration of Ang-2 was assessed in culture medium of pulmonary microvascular endothelial cells in the presence or absence of Gram-positive bacteria cell wall components [lipoteichoic acid (LTA) and peptidoglycan (PGN)] stimulation at different time points ranging from 15 minutes to 24 hours. Constitutive and LTA-PGN-stimulated Ang-2 level changes were also assessed after cells were pretreated with different pathway inhibitors for 1 hour.</p><p>RESULTS: Two distinctive mechanisms of Ang-2 secretion, constitutive and stimulated secretion, were identified. Constitutive secretion resulted in slow but continuous increase in Ang-2 in culture medium over time. It was regulated by 3'5'-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-Ca(2+) and nitric oxide (NO)-3'5'-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)-Ca(2+) pathways and partially regulated by N-ethyl-maleimide-sensitive factor-Ca(2+) pathways. LTA-PGN stimulation caused rapid and potent increase followed by gradual decrease of Ang-2. It was partially regulated by both Ral A-phospholipase D and NSF-Ca(2+) pathways.</p><p>CONCLUSIONS: We demonstrated characteristics and involved pathways for two distinctive secretory mechanisms, constitutive and stimulated, of Ang-2 in pulmonary microvascular endothelial cells. Considering the close correlation of Ang-2 with sepsis outcomes, our findings provide a better understanding of an important mechanism associated with sepsis pathophysiology and identify possible therapeutic targets to improve outcomes in the potentially lethal disease.</p>}},
author = {{Lee, Ji Young and Linge, Helena M and Ochani, Kanta and Lin, Ke and Miller, Edmund J}},
issn = {{1432-1750}},
language = {{eng}},
month = {{09}},
number = {{7}},
pages = {{335--345}},
publisher = {{Springer}},
series = {{Lung}},
title = {{Regulation of angiopoietin-2 secretion from human pulmonary microvascular endothelial cells}},
url = {{http://dx.doi.org/10.1080/01902148.2016.1218977}},
doi = {{10.1080/01902148.2016.1218977}},
volume = {{42}},
year = {{2016}},
}