Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USA.
Drug Safety Sciences, Johnson & Johnson, Raritan, New Jersey, USA.
Toxicol Sci. 2017 May 1;157(1):222-234. doi: 10.1093/toxsci/kfx032.
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.
氮芥（NM）诱导的肺损伤与促炎/细胞毒性 M1 和抗炎/伤口修复 M2 巨噬细胞的积累有关，这些细胞已被牵连到组织损伤和修复中。在此，我们分析了组蛋白去乙酰化酶（HDAC）抑制剂丙戊酸（VPA）对 NM 反应性肺巨噬细胞的影响。用 NM（0.125mg/kg，腹腔内）处理大鼠导致肺结构改变和富含巨噬细胞的炎症细胞浸润，在 3 天和 7 天。这伴随着增殖标志物 PCNA、氧化应激标志物 CYPb5、HO-1 和 MnSOD 的表达。VPA（300mg/kg/天；腹腔内）的给药在 NM 后 30 分钟开始，可减少 PCNA、CYPb5、HO-1 和 MnSOD 的增加。这与肺中不成熟的 CD11b+CD43+M1 巨噬细胞的增加以及 NM 后 3 天成熟的 CD11b+CD43-M2 巨噬细胞的减少有关，这表明成熟和表型转换延迟。VPA 还减弱了 NM 诱导的肺 iNOS+和 CCR2+M1 巨噬细胞的增加，这一反应与 NOS2、IL12B、PTGS2、MMP-9 和 CCR2 表达的下调有关。相反，在 VPA 后，CD68+、CD163+和 ATR-1α+M2 巨噬细胞的数量增加，同时还增加了 IL10、ApoE 和 ATR-1A 的表达。NM 暴露导致肺中的 HDAC 活性增加和 HDAC2 以及组蛋白 H3K9 的乙酰化增加。虽然 VPA 减弱了 NM 对 HDAC2 表达的影响，但组蛋白 H3K9 的乙酰化增加了。这些数据表明，组蛋白乙酰基转移酶和去乙酰化酶之间平衡的改变有助于 NM 暴露后肺巨噬细胞的成熟和激活。
