Abraham E, Coulson W F, Schwartz M D, Allbee J
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Centre, Denver 80262.
Clin Exp Immunol. 1994 Oct;98(1):29-34. doi: 10.1111/j.1365-2249.1994.tb06602.x.
Acute lung injury frequently develops following haemorrhage, and is characterized by increased proinflammatory cytokine levels and massive neutrophil accumulation in the lung. Blood loss produces rapid increases in tumour necrosis factor-alpha (TNF-alpha) mRNA expression among pulmonary cell populations which precede the development of lung injury. In order to examine the role of TNF-alpha in producing acute inflammatory lung injury, we treated mice following haemorrhage and resuscitation with a TNF antagonist, composed of soluble dimeric human p80 TNF receptor linked to the Fc region of human IgG1 (sTNFR:Fc). Therapy with sTNFR:Fc prevented the post-haemorrhage increases in circulating and pulmonary TNF-alpha levels normally found following blood loss. Administration of sTNFR:Fc also diminished the increase in IL-1 beta, IL-6, TNF-alpha and interferon-gamma (IFN-gamma) mRNA normally found in the lungs following haemorrhage. However, therapy with sTNFR:Fc was not associated with improvement in the histologic parameters of post-haemorrhage lung injury, such as neutrophil infiltration and interstitial oedema. In contrast to the effects of sTNFR:Fc on cytokine mRNA levels among intraparenchymal pulmonary mononuclear cells, such therapy following haemorrhage was associated with increased amounts of mRNA for TNF-alpha among peripheral blood mononuclear cells, as well as increased IFN-gamma titres in serum and bronchoalveolar lavage (BAL) specimens. These results indicate that therapy with sTNFR:Fc in the post-haemorrhage period, although capable of decreasing proinflammatory cytokine expression in the lungs, does not prevent the development of acute lung injury in this setting.
急性肺损伤常发生于出血后，其特征为促炎细胞因子水平升高以及肺内大量中性粒细胞积聚。失血导致肺细胞群体中肿瘤坏死因子-α（TNF-α）mRNA表达迅速增加，这早于肺损伤的发生。为了研究TNF-α在急性炎症性肺损伤中的作用，我们在小鼠出血和复苏后用一种TNF拮抗剂进行治疗，该拮抗剂由与人类IgG1的Fc区相连的可溶性二聚体人类p80 TNF受体组成（sTNFR:Fc）。用sTNFR:Fc治疗可防止出血后循环和肺内TNF-α水平如正常失血后那样升高。给予sTNFR:Fc还可减轻出血后肺内通常出现的IL-1β、IL-6、TNF-α和干扰素-γ（IFN-γ）mRNA的增加。然而，用sTNFR:Fc治疗与出血后肺损伤的组织学参数改善无关，如中性粒细胞浸润和间质水肿。与sTNFR:Fc对肺实质内肺单核细胞中细胞因子mRNA水平的影响相反，出血后这种治疗与外周血单核细胞中TNF-α mRNA量增加以及血清和支气管肺泡灌洗（BAL）标本中IFN-γ滴度增加有关。这些结果表明，出血后用sTNFR:Fc治疗，尽管能够降低肺内促炎细胞因子的表达，但在这种情况下并不能预防急性肺损伤的发生。
