Department of Clinical Sciences, Malmö, Section for Surgery, Malmö, Lund University, Sweden.
Am J Physiol Lung Cell Mol Physiol. 2013 Feb 15;304(4):L221-9. doi: 10.1152/ajplung.00199.2012. Epub 2012 Dec 14.
Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal sepsis. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets. Gene expression of CXC chemokines, tumor necrosis factor-α (TNF-α), and CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils, edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably, GGTI-2133 abolished CLP-induced formation of CXC chemokines, TNF-α, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl transferase inhibition had no effect on sepsis-induced platelet shedding of CD40L. In addition, inhibition of geranylgeranyl transferase markedly decreased CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl transferase is an important regulator of CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl transferase might be a potent way to attenuate acute lung injury in abdominal sepsis.
中性粒细胞的过度积累是脓毒症性肺损伤的一个重要组成部分，尽管中性粒细胞浸润肺部的信号机制仍不明确。在本研究中，我们假设香叶基香叶基化可能调节腹部脓毒症中的炎症反应。雄性 C57BL/6 小鼠在盲肠结扎和穿孔 (CLP) 前接受香叶基香叶基转移酶抑制剂 GGTI-2133 处理。采集支气管肺泡灌洗液和肺组织，分析中性粒细胞浸润、水肿和 CXC 趋化因子形成。采集血液，分析中性粒细胞上的 Mac-1 和血小板上的 CD40L。通过定量 RT-PCR 测定分离的肺泡巨噬细胞中 CXC 趋化因子、肿瘤坏死因子-α (TNF-α) 和 CCL2 趋化因子的基因表达。GGTI-2133 的给药显著降低了 CLP 诱导的中性粒细胞浸润、水肿和肺部组织损伤。CLP 明显上调了中性粒细胞上的 Mac-1。香叶基香叶基转移酶抑制剂减少了体内 CLP 诱导的中性粒细胞上 Mac-1 的上调，但对体外趋化因子诱导的分离中性粒细胞上 Mac-1 的表达没有影响。值得注意的是，GGTI-2133 消除了 CLP 诱导的肺泡巨噬细胞中 CXC 趋化因子、TNF-α 和 CCL2 在肺中的形成。香叶基香叶基转移酶抑制剂对脓毒症诱导的血小板脱落 CD40L 没有影响。此外，香叶基香叶基转移酶抑制剂显著降低了体外 CXC 趋化因子触发的中性粒细胞趋化性。总之，我们的研究结果表明，香叶基香叶基转移酶是肺部 CXC 趋化因子产生和中性粒细胞募集的重要调节剂。我们得出结论，抑制香叶基香叶基转移酶可能是减轻腹部脓毒症急性肺损伤的有效方法。
