严重急性呼吸综合征患者尸解肺标本的病理改变和致病机制研究

Lung pathology and pathogenesis of severe acute respiratory syndrome:a report of six full autopsies

目的研究严重急性呼吸综合征(SARS)患者尸解肺标本的病理改变和致病机制。方法观察了2003年4—7月期间死于SARS的6例患者的肺标本,并采用光镜、电镜、Masson三色染色和免疫组织化学染色方法(EnVision法)进行研究。结果肺标本的病理形态改变:(1)6例的双肺均可见到弥漫性实变病灶,肺重量明显增加;(2)6例均可见到弥漫性肺泡损伤,包括透明膜形成、肺泡腔内水肿/出血、纤维素沉积和肺泡上皮细胞脱屑,AE1/AE3免疫组织化学染色显示肺泡上皮细胞的完整性明显破坏;(3)Ⅱ型肺泡上皮细胞轻度增生,有一定异型性,细胞体积增大,胞质呈双染性和颗粒状,胞质内可见小脂肪空泡聚集(5/6);(4)6例中有5例可见巨细胞在肺泡内浸润,巨细胞大多AE1/AE3阳性(5/6),少数CD68阳性(2/6);(5)组织学形态和免疫组织化学染色证实肺泡腔内和肺泡间隔内有多量巨噬细胞浸润(6/6);(6)6例中有5例可见巨噬细胞噬红细胞象;(7)6例中有5例可见肺纤维化,包括肺泡间隔和肺间质增宽(5/6)、肺泡腔内渗出物机化(6/6)和胸膜增厚(4/6)。Masson三色染色证实胶原纤维明显增生,免疫组织化学染色显示大多数为Ⅲ型胶原。光镜和免疫组织化学染色显示5例有明显的成纤维细胞/肌纤维母细胞增生灶;(8)5例可见支气管黏膜鳞状上皮化生;(9)6例患者均可见血栓;(10)2例同时合并其他感染,1例合并细菌感染,另1例合并真菌感染。此外,电镜发现在肺泡上皮细胞和肺血管内皮细胞的胞质内有冠状病毒样颗粒。结论SARS冠状病毒直接损伤肺泡上皮细胞、巨噬细胞明显浸润和成纤维细胞/肌纤维母细胞显著增生在SARS的致病机制中起重要作用。

Objective Severe acute respiratory syndrome （SARS） is an emerging infectious disease that first manifested in humans in November 2002. The SARS-associated coronavirus （SARS-CoV） has been identified as the causal agent, but the pathology and pathogenesis are still not quite clear. Methods Post- mortem lung samples from six patients who died from SARS from April to July 2003 were studied by light and electron microscopy, Masson triehromal staining and immunohistochemistry. Evidence of infection with the SARS-CoV was determined by reverse-transcription PCR （RT-PCR）, serological examination and electron microscopy. Results Four of six patients had serological and RT-PCR evidence of recent infection of SARS- CoV. Morphologic changes are summarized as follows ： （ 1 ） Diffuse and bilateral lung consolidation was seen in all patients （ 6/6 ） with increasing lung weight. （ 2 ） Diffuse alveolar damage was universal （ 6/6 ） with hyaline membrane formation （ 6/6 ） , intra-alveolar edema/hemorrhage （ 6/6 ）, fibrin deposition （ 6/6 ）, pneumocyte desquamation （6/6）. A marked disruption in the integrity of the alveolar epithelium was confirmed by immunostaining for the epithelial marker AE1/AE3 （ 6/6 ）. （ 3 ） Type 11 pneumocytes, with mild hyperplasia, atypia, cytomegaly with granular amphophilic cytoplasm and intracytoplasmic lipid accumulation （5/6）. （4）Giant cells in the alveoli were seen in five of 6 patients（5/6）, most of which were positive for the epithelial marker AE1/AE3 （5/6） , but some cells were positive for the macrophage marker CD68 （2/6）. （5） A pronounced increase of macrophages were seen in the alveoli and the interstitium of the lung（6/6） , which was confirmed by histological study and immunohistochemistry. （6）Haemophagoeytosis was present in five of the 6 patients （5/6）. （7）Lung fibrosis was seen in five patients （5/6） , with alveolar septa and interstitium thickening（5/6 ）, intraalveolar organizing exudates （ 6/6 ） and pleura thickening （ 4/ 6）. Proliferation of collagen was confirmed by Masson trichromal staining, most of which was type Ⅲ collagen by immunostaining. The formation of distinctive fibroblast/myofibroblast foci was seen in five patients （5/6） by light microscopy and immunochemistry. （8） Squamous metaplasia of bronchial mucosa was seen in five patients （ 5/6 ）. （9） Thrombi was seen in all patients （ 6/6 ）. （ 10 ） Accompanying infection was present in two patients, one was bacteria, the other was fungus. In addition, electron microscopy revealed viral particles in the cytoplasm of alveolar epithelial cells and endothelial cells corresponding to coronavirus. Conclusion Direct injury of SARS-CoV on alveolar epithelium, prominent macrophage infiltration and distinctive fibroblast/myofibroblast proliferation may play major roles in the pathogenesis of SARS.