Regulation of Nitrogen Mustard-Induced Lung Macrophage Activation by Valproic Acid, a Histone Deacetylase Inhibitor

Abstract

Nitrogen mustard (NM)-induced lung injury is associated with an accumulation of proinflammatory/cytotoxic M1 and antiinflammatory/wound repair M2 macrophages, which have been implicated in tissue injury and repair. Herein, we analyzed the effects of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor with antiinflammatory and antioxidant activity, on lung macrophages responding to NM. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in structural alterations in the lung and a macrophage-rich inflammatory cell infiltrate, at 3 d and 7 d. This was accompanied by expression of PCNA, a marker of proliferation, and CYPb5, HO-1, and MnSOD, markers of oxidative stress. Administration of VPA (300 mg/kg/day; i.p.), beginning 30 min after NM, reduced increases in PCNA, CYPb5, HO-1, and MnSOD. This was associated with increases in immature CD11b+CD43+ M1 macrophages in the lung, and decreases in mature CD11b+CD43- M2 macrophages 3 d post NM, suggesting delayed maturation and phenotypic switching. VPA also attenuated NM-induced increases in lung iNOS+ and CCR2+ M1 macrophages, a response correlated with downregulation of NOS2, IL12B, PTGS2, MMP-9, and CCR2 expression. Conversely, numbers of CD68+, CD163+ , and ATR-1α+ M2 macrophages increased after VPA, along with the expression of IL10, ApoE, and ATR-1A. NM exposure resulted in increased HDAC activity and upregulation of HDAC2 and acetylated H3K9 in the lung. Whereas VPA blunted the effects of NM on HDAC2 expression, histone H3K9 acetylation increased. These data suggest that alterations in the balance between histone acetylases and deacetylases contribute to lung macrophage maturation and activation following NM exposure.

Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells

“…A rat model of spinal cord injury showed a diminished macrophage infiltration due to a reduced inflammation, which provided neuroprotection [72, 73]; likewise, VPA also reduced the macrophage infiltration in a mouse model of nephropathy [74]. In addition, a rat model of lung injury demonstrated that VPA impaired M1 macrophages and the expression of the antigen of nuclear proliferation and of oxidative stress markers, while favoring the proliferation of M2 macrophages; this was related to reduced inflammation and increased tissue repair [75].…”

Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages

“…Its effects on M2s have not been elucidated although it has been shown to inhibit tumor growth enhancement induced by decoy receptor 3 which promotes M2 TAM infiltration [ 100 ]. Additionally, in a nitrogen mustard-induced lung injury model, VPA decreases iNOS + CCR2 + macrophages and increases CD68 + , CD163 + , and ATR-1a + macrophages in lung tissue [ 101 ]. In M1 in vitro models, VPA has been shown to generally decrease M1 markers and phenotype [ 88 , 102 , 103 ].…”

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