Histone Deacetylase Inhibitor Treatment Attenuates MAP Kinase Pathway Activation and Pulmonary Inflammation Following Hemorrhagic Shock in a Rodent Model

Abstract

Background Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. We have previously shown that treatment with histone deacetylase inhibitors (HDACIs) significantly improves survival in lethal models (60% blood loss) of hemorrhage. The aim of the current study was to examine whether these protective effects were due to attenuation of mitogen activated protein kinase (MAPK) signaling pathways, which are known to promote inflammation and apoptosis. Study Design Wistar-Kyoto rats (250–300g) were subjected to 40% blood loss and randomized to treatment with: 1) HDACI valproic acid (VPA 300mg/kg IV; volume = 0.75 ml/kg), or 2) vehicle control (0.75 ml/kg of 0.9% saline). Animals were sacrificed at 1, 4 and 20 hours (n=3–4/group/timepoint), and lung samples were analyzed by Western blotting for expression of active (phosphorylated) and inactive forms of c-Jun N terminal Kinase (JNK) and p38 MAPK. Myeloperoxidase (MPO) activity was measured in lung tissue 20 hours after hemorrhage as a marker of neutrophil infiltration. Normal animals (n=3) served as shams. Results Hemorrhaged animals demonstrated significant increases in phosphorylated p38 at 1 hour, phosphorylated JNK at 4 hours, and increased MPO activity at 20 hours (p<0.05 compared to sham). VPA treatment significantly (p <0.05) attenuated all of these changes. Conclusions Hemorrhagic shock activates pro-inflammatory MAPK signaling pathways and promotes pulmonary neutrophil infiltration, affects that are significantly attenuated by VPA treatment. This may represent a key mechanism through which HDACIs decrease organ damage and promote survival in hemorrhagic shock.

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

“…Thus, Aza+TSA might be considered as putative anti-inflammatory treatment that modulates LPS-stimulated inflammatory responses and activates an array of key anti-inflammatory signaling pathways. Recent data indicate that members of the MAPK family are involved in modulating mRNA stability and/or translation of several genes (Kochanek et al, 2012;Rajasingh et al, 2006). Our data show that treatment with Aza+TSA abrogated the LPS-TLR4-MAPK pathway, which initiated an inflammatory cascade, and is known to potentiate apoptotic signals within the macrophages.…”

“…We and others and have shown previously that members of the MAPK family are involved in modulating mRNA stability and/or translation of several pro-inflammatory genes (Kochanek et al, 2012;Rajasingh et al, 2006). Studies have shown that activation (i.e.…”

“…We chose to study the macrophages because of their role in orchestrating inflammation (Kochanek et al, 2012;Song et al, 2001). We focused on the combined treatment with epigenetic modifiers Aza and TSA (hereafter referred to as Aza+TSA) that induce a protective mechanism through p38MAPK-HuR-TNFα and STAT3-Bcl2 signaling pathways during inflammatory and antiinflammatory responses, respectively.…”

Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease

“…Others have found that VPA can reduce lung inflammation in acute lung injury and hemorrhagic shock models. 23,24 This difference may reflect the level of inflammation in chronic disease and the treatment regimen used. We did however find a strong therapeutic effect on airway remodeling.…”

Nanostructured Lipid Carriers Containing a High Percentage of a Pluronic Copolymer Increase the Biodistribution of Novel PDE4 Inhibitors for the Treatment of Traumatic Hemorrhage

“…DSM-RX78 and EFB-1 were synthesized as described previously. 16 Partition Coefficients (log P ) of PDE4 Inhibitors Octanol or squalene (1 ml) including predetermined concentrations of DSM-RX78, EFB-1, or their metabolite, SMP-3 ( Fig. 1), was mixed with water (1 ml).…”