Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China.
Department of Respiratory Medicine, Yixing People Hospital, Affiliated Jiangsu University, No. 75 Tongzhenguan Road, Yixing 214200, Jiangsu, PR China.
Int Immunopharmacol. 2019 May;70:208-215. doi: 10.1016/j.intimp.2019.02.039. Epub 2019 Mar 6.
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is of concern because of its propensity for rapid deterioration and high mortality. Its aetiology and mechanism are still unclear. The aims of this study were to clarify the pathophysiology differences between AE-IPF and stable IPF (S-IPF) by comparing the serum levels of various cytokines and chemokines in the two groups and to identify those involvement in the occurrence of acute exacerbation and associated with mortality.
The study included 28 patients with AE-IPF, 32 patients with S-IPF, and 18 healthy control subjects. We measured the serum cytokine and chemokine levels in all cases by multiplex assay. Serum levels of cytokines and chemokines were compared between AE-IPF and S-IPF subjects. Logistic regression analysis was applied to identify the ability of these variables to predict acute exacerbation. Kaplan-Meier curves were used to analyse survival and Cox proportional hazard regression was used to identify predictors of survival.
Levels of several cytokines and chemokines were significantly higher in both patient groups with IPF (with the exception of interleukin-2 [IL-2], chemokine cc-motif ligand 3, and RANTES [regulation upon activation normal T-cell express sequence]) than in healthy controls. Serum IL-1β (p = 0.008) and interferon (IFN)-γ (p = 0.007) levels tended to be higher in patients with AE-IPF than in those with S-IPF. The concentration of chemokine cc-motif ligand (CCL) 2 was significantly higher in bronchoalveolar lavage fluid than in serum (p = 0.001). Higher C-reactive protein, lactate dehydrogenase, percent forced vital capacity, percent diffusing capacity of the lung for carbon monoxide, and IFN-γ values in the patients with IPF were correlated with acute exacerbation status, with respective odds ratios of 1.241 (p = 0.011), 1.050 (p = 0.004), 1.043 (p = 0.001), 0.927 (p = 0.014), and 0.929 (p = 0.020). Acute exacerbation status was associated with an increased risk of mortality (hazard ratio 0.107, 95% confidence interval 0.036-0.314; p < 0.001). Univariate Cox regression demonstrated an association of IFN-γ, CCL2, C-X-C motif chemokine 10 (CXCL10) and sCD163 levels with an increased mortality risk (p = 0.015, p = 0.002, p = 0.001, and p = 0.030, respectively).
Our data demonstrate that serum levels of some pro-inflammatory cytokines and macrophage chemokines are upregulated during acute exacerbations of IPF and that these exacerbations are associated with the serum IFN-γ level. Chemokines and protein such as sCD163, CCL2, and CXCL10 are associated with activation of macrophages and may have a serious impact on overall survival in patients with IPF.
特发性肺纤维化（IPF）的急性加重令人关注，因为其具有迅速恶化和高死亡率的倾向。其病因和发病机制仍不清楚。本研究旨在通过比较两组患者的血清细胞因子和趋化因子水平，阐明 AE-IPF 和稳定型 IPF（S-IPF）之间的病理生理学差异，并确定那些与急性加重的发生及其与死亡率相关的因素。
纳入 28 例 AE-IPF 患者、32 例 S-IPF 患者和 18 例健康对照者。我们通过多重检测法测量了所有病例的血清细胞因子和趋化因子水平。比较 AE-IPF 和 S-IPF 患者的血清细胞因子和趋化因子水平。应用逻辑回归分析确定这些变量预测急性加重的能力。采用 Kaplan-Meier 曲线分析生存情况，采用 Cox 比例风险回归分析确定生存的预测因素。
除白细胞介素 2（IL-2）、趋化因子 C 基序配体 3 和调节正常 T 细胞表达序列）外，两组 IPF 患者的几种细胞因子和趋化因子水平均显著高于健康对照组。AE-IPF 患者的血清白介素 1β（p=0.008）和干扰素（IFN）-γ（p=0.007）水平倾向于高于 S-IPF 患者。趋化因子 C 基序配体（CCL）2 在支气管肺泡灌洗液中的浓度明显高于血清（p=0.001）。IPF 患者的 C 反应蛋白、乳酸脱氢酶、用力肺活量百分比、一氧化碳弥散量百分比和 IFN-γ值升高与急性加重状态相关，各自的比值比分别为 1.241（p=0.011）、1.050（p=0.004）、1.043（p=0.001）、0.927（p=0.014）和 0.929（p=0.020）。急性加重状态与死亡率升高相关（风险比 0.107，95%置信区间 0.036-0.314；p<0.001）。单变量 Cox 回归表明 IFN-γ、CCL2、C-X-C 基序趋化因子 10（CXCL10）和 sCD163 水平与死亡率升高相关（p=0.015、p=0.002、p=0.001 和 p=0.030）。
我们的数据表明，一些促炎细胞因子和巨噬细胞趋化因子的血清水平在 IPF 的急性加重期间上调，并且这些加重与血清 IFN-γ 水平相关。趋化因子和蛋白，如 sCD163、CCL2 和 CXCL10，与巨噬细胞的激活相关，可能对 IPF 患者的总体生存产生严重影响。
