Venosa Alessandro, Malaviya Rama, Gow Andrew J, Hall Leroy, Laskin Jeffrey D, Laskin Debra L
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Piscataway, New Jersey;
Drug Safety Sciences, Johnson & Johnson, Raritan, New Jersey; and.
Am J Physiol Lung Cell Mol Physiol. 2015 Dec 15;309(12):L1487-98. doi: 10.1152/ajplung.00276.2015. Epub 2015 Oct 16.
Nitrogen mustard (NM) is a vesicant that causes lung injury and fibrosis, accompanied by a persistent macrophage inflammatory response. In these studies we analyzed the spleen as a source of these cells. Splenectomized (SPX) and sham control rats were treated intratracheally with NM (0.125 mg/kg) or PBS control. Macrophage responses were analyzed 1-7 days later. Splenectomy resulted in an increase in lung macrophages expressing CCR2, but a decrease in ATR-1α(+) cells, receptors important in bone marrow and spleen monocyte trafficking, respectively. Splenectomy was also associated with an increase in proinflammatory M1 (iNOS(+), CD11b(+)CD43(+)) macrophages in lungs of NM-treated rats, as well as greater upregulation of iNOS and COX-2 mRNA expression. Conversely, a decrease in CD11b(+)CD43(-) M2 macrophages was observed in SPX rats, with no changes in CD68(+), CD163(+), CD206(+), or YM-1(+) M2 macrophages, suggesting distinct origins of M2 subpopulations responding to NM. Macrophage expression of M2 genes including IL-10, ApoE, PTX-2, PTX-3, 5-HT2α, and 5-HT7 was also reduced in NM-treated SPX rats compared with shams, indicating impaired M2 activity. Changes in lung macrophages responding to NM as a consequence of splenectomy were correlated with exacerbated tissue injury and more rapid fibrogenesis. These data demonstrate that the spleen is a source of a subset of M2 macrophages with anti-inflammatory activity; moreover, in their absence, proinflammatory/cytotoxic M1 macrophages predominate in the lung, resulting in heightened pathology. Understanding the origin of macrophages and characterizing their phenotype after vesicant exposure may lead to more targeted therapeutics aimed at reducing toxicity and disease pathogenesis.
氮芥（NM）是一种会导致肺损伤和纤维化的发泡剂，伴有持续的巨噬细胞炎症反应。在这些研究中，我们分析了脾脏作为这些细胞来源的情况。对脾切除（SPX）大鼠和假手术对照大鼠经气管内给予NM（0.125mg/kg）或PBS对照。1至7天后分析巨噬细胞反应。脾切除导致肺中表达CCR2的巨噬细胞增加，但ATR-1α(+)细胞减少，这两种受体分别在骨髓和脾脏单核细胞运输中起重要作用。脾切除还与NM处理大鼠肺中促炎M1（诱导型一氧化氮合酶（iNOS）(+)、CD11b(+)CD43(+)）巨噬细胞增加有关，以及iNOS和环氧化酶-2（COX-2）mRNA表达的更大上调。相反，在SPX大鼠中观察到CD11b(+)CD43(-) M2巨噬细胞减少，而CD68(+)、CD163(+)、CD206(+)或Ym-1(+) M2巨噬细胞无变化，这表明对NM作出反应的M2亚群有不同的来源。与假手术组相比，NM处理的SPX大鼠中包括白细胞介素-10（IL-10）、载脂蛋白E（ApoE）、肺炎衣原体毒素2（PTX-2）、肺炎衣原体毒素3（PTX-3）、5-羟色胺2α（5-HT2α）和5-羟色胺7（5-HT7）在内的M2基因的巨噬细胞表达也降低，表明M2活性受损。脾切除导致对NM作出反应的肺巨噬细胞变化与加剧的组织损伤和更快的纤维化相关。这些数据表明，脾脏是具有抗炎活性的M2巨噬细胞亚群的来源；此外，在没有这些细胞的情况下，促炎/细胞毒性M1巨噬细胞在肺中占主导地位，导致病理状况加剧。了解巨噬细胞的来源并在发泡剂暴露后对其表型进行表征，可能会带来更有针对性的治疗方法，以降低毒性和疾病发病机制。
