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Complete and Partial Aortic Occlusion for the Treatment of Hemorrhagic Shock in Swine
Published on: August 24, 2018
VALPROIC ACID INHIBITS CLASSICAL MONOCYTE-DERIVED TISSUE FACTOR AND ALLEVIATES HEMORRHAGIC SHOCK-INDUCED ACUTE LUNG
Lina Shao, Bing Wu1, Chang Liu1
1Emergency Department, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
Abstract:
Background: Monocytes and monocyte-derived tissue factor (TF) promote the development of sepsis-induced acute lung injury (ALI). Classical monocytes (C-Mcs) can be induced to express TF. Valproic acid (VPA) alleviates hemorrhagic shock (HS)-induced ALI (HS/ALI) and inhibits TF expression in monocytes. We hypothesized that C-Mcs and C-Mc-derived TF promoted HS/ALI and that VPA could inhibit C-Mc-derived TF expression and attenuate HS/ALI. Methods: Wistar rats and THP-1 cells were used to evaluate our hypothesis. Monocyte subtypes were analyzed by flow cytometry; mRNA expression was measured by fluorescence quantitative polymerase chain reaction; protein expression was measured by Western blotting, immunofluorescence, or immunohistology; inflammatory cytokines levels were measured by enzyme-linked immunosorbent assay; and ALI scores were used to determine the degree of ALI. Results: The blood %C-Mcs and C-Mcs/non-C-Mcs ratios, monocyte TF levels, serum and/or lung inflammatory cytokine levels, and ALI scores of HS rats were significantly increased ( P < 0.05). After monocyte depletion and thrombin inhibition, the inflammatory cytokine levels and ALI scores were significantly decreased ( P < 0.05). VPA reduced the %C-Mcs and C-Mc/non-C-Mc ratios, TF expression, inflammatory cytokine levels, and ALI scores during HS ( P < 0.05) and inhibited HS-induced monocyte Egr-1 and p-ERK1/2 expression ( P < 0.05). VPA inhibited hypoxia-induced TF expression in THP-1 cells by regulating the p-ERK1/2-Egr-1 axis. Conclusion: C-Mcs and C-Mc-derived TF accelerate the development of HS/ALI by increasing thrombin production. VPA inhibits HS-induced C-Mc production of TF by regulating the p-ERK1/2-Egr-1 axis and alleviates HS/ALI.
Insights
Classical monocytes and their tissue factor promote hemorrhagic shock-induced acute lung injury. Valproic acid reduces monocyte tissue factor and alleviates this injury by targeting the p-ERK1/2-Egr-1 pathway.
Area of Science:
- Immunology
- Pathophysiology
- Pharmacology
Background:
- Monocytes and tissue factor (TF) are implicated in sepsis-induced acute lung injury (ALI).
- Classical monocytes (C-Mcs) can express TF, contributing to injury.
- Valproic acid (VPA) is known to alleviate hemorrhagic shock-induced ALI (HS/ALI) and inhibit monocyte TF expression.
Purpose of the Study:
- To investigate the role of C-Mcs and C-Mc-derived TF in HS/ALI.
- To determine if VPA inhibits C-Mc-derived TF expression and attenuates HS/ALI.
Main Methods:
- Utilized Wistar rats and THP-1 cells.
- Analyzed monocyte subtypes via flow cytometry.
- Quantified mRNA and protein expression (TF, Egr-1, p-ERK1/2) using PCR, Western blotting, and immunofluorescence.
- Measured inflammatory cytokines (ELISA) and ALI scores.
Main Results:
- HS rats showed increased C-Mcs, TF levels, inflammatory cytokines, and ALI scores.
- Monocyte depletion and thrombin inhibition significantly reduced inflammation and ALI.
- VPA decreased C-Mcs, TF expression, inflammatory cytokines, and ALI scores in HS rats.
- VPA inhibited HS-induced monocyte Egr-1 and p-ERK1/2 expression and hypoxia-induced TF expression in THP-1 cells via the p-ERK1/2-Egr-1 axis.
Conclusions:
- C-Mcs and TF accelerate HS/ALI development by increasing thrombin production.
- VPA mitigates HS/ALI by inhibiting TF production in C-Mcs through the p-ERK1/2-Egr-1 pathway.
