Meduri G U, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A
Department of Medicine, University of Tennessee Medical Center, Memphis, USA.
Chest. 1995 Nov;108(5):1303-14. doi: 10.1378/chest.108.5.1303.
Inflammatory cytokines (ICs) are important modulators of injury and repair. ICs have been found to be elevated in the BAL of patients with both early and late ARDS. We tested the hypothesis that recurrent injury to the alveolocapillary barrier and amplification of intra-alveolar fibroproliferation observed in nonresolving ARDS is related to a persistent inflammatory response. For this purpose, we obtained serial measurements of BAL IC and correlated these levels with lung injury score (LIS), BAL indexes of endothelial permeability (albumin, total protein [TP]), and outcome.
We prospectively studied 27 consecutive patients with severe medical ARDS. Using enzyme-linked immunosorbent assay methods, levels of tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL) 1 beta, 2, 4, 6, and 8 were measured at frequent intervals in both plasma and BAL. In 22 patients, bilateral BAL was obtained on day 1 of ARDS and at weekly intervals when possible. Right and left BALs were analyzed separately for IC levels, total cell count and differential, albumin, TP, and quantitative bacterial cultures.
On day 1 of ARDS, the 10 nonsurvivors had significantly higher (p = 0.0002) BAL TNF-alpha, IL-1 beta, IL-6, and IL-8 levels, which remained persistently elevated over time, indicating a continuous injury process. In contrast, the 12 survivors had a lesser elevation and a rapid reduction over time. Initial BAL IL-2 and IL-4 levels were significantly higher in patients with sepsis (p = 0.006); both increased over time in survivors and nonsurvivors. BAL levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 correlated with BAL albumin and TP concentrations but not with LIS or ratio of arterial oxygen tension to inspired oxygen concentration. BAL: plasma ratios were elevated for all measured cytokines, suggesting a pulmonary origin. On day 1 of ARDS, nonsurvivors had significantly higher (p = 0.04) BAL: plasma ratios for TNF-alpha, IL-1 beta, IL-6, and IL-8. Over time, BAL:plasma ratios for TNF-alpha, IL-1 beta and IL-6 remained elevated in nonsurvivors and decreased in survivors.
Our findings indicate that an unfavorable outcome in ARDS is associated with an initial, exaggerated, pulmonary inflammatory response that persists unabated over time. Plasma IC levels parallel changes in BAL IC levels. The BAL:plasma ratio results suggest, but do not prove, a pulmonary origin for IC production. BAL TNF-alpha, IL-1 beta, and IL-8 levels correlated with BAL indices of endothelial permeability. In survivors, reduction in BAL IC levels over time was associated with a decline in BAL albumin and TP levels, suggesting effective repair of the endothelial surface. These findings support a causal relationship between degree and duration of lung inflammation and progression of fibroproliferation in ARDS.
炎性细胞因子（ICs）是损伤和修复的重要调节因子。已发现早期和晚期急性呼吸窘迫综合征（ARDS）患者的支气管肺泡灌洗（BAL）液中ICs水平升高。我们检验了以下假设：在未缓解的ARDS中观察到的肺泡毛细血管屏障反复损伤和肺泡内纤维增殖的放大与持续的炎症反应有关。为此，我们对BAL IC进行了系列测量，并将这些水平与肺损伤评分（LIS）、内皮通透性的BAL指标（白蛋白、总蛋白[TP]）及预后相关联。
我们前瞻性地研究了27例连续的重症医学性ARDS患者。采用酶联免疫吸附测定方法，在血浆和BAL液中定期测量肿瘤坏死因子-α（TNF-α）及白细胞介素（IL）1β、2、4、6和8的水平。在22例患者中，于ARDS第1天及尽可能每周一次获取双侧BAL液。分别分析左右两侧BAL液的IC水平、总细胞计数及分类、白蛋白、TP和定量细菌培养结果。
ARDS第1天，10例非存活者的BAL液TNF-α、IL-1β、IL-6和IL-8水平显著更高（p = 0.0002），且随时间持续升高，表明存在持续的损伤过程。相比之下，12例存活者的升高幅度较小且随时间迅速下降。脓毒症患者初始BAL液IL-2和IL-4水平显著更高（p = 0.006）；存活者和非存活者的这两种细胞因子水平均随时间升高。BAL液TNF-α、IL-1β、IL-6和IL-8水平与BAL液白蛋白和TP浓度相关，但与LIS或动脉血氧分压与吸入氧浓度之比无关。所有测量的细胞因子的BAL液：血浆比值均升高，提示其来源于肺。ARDS第1天，非存活者的BAL液：血浆TNF-α、IL-1β、IL-6和IL-8比值显著更高（p = 0.04）。随时间推移，非存活者的BAL液：血浆TNF-α、IL-1β和IL-6比值持续升高，而存活者则下降。
我们的研究结果表明，ARDS不良预后与初始的、过度的肺部炎症反应有关，且该反应随时间持续未减。血浆IC水平与BAL液IC水平变化平行。BAL液：血浆比值结果提示但未证实IC产生于肺。BAL液TNF-α、IL-1β和IL-8水平与内皮通透性的BAL指标相关。在存活者中，BAL液IC水平随时间降低与BAL液白蛋白和TP水平下降相关，提示内皮表面得到有效修复。这些发现支持了ARDS中肺炎症的程度和持续时间与纤维增殖进展之间的因果关系。
