de Santi M M, Martorana P A, Cavarra E, Lungarella G
Institute of Pathological Anatomy, University of Siena, Italy.
Lab Invest. 1995 Jul;73(1):40-7.
According to a current hypothesis, pulmonary emphysema results from damage to the elastic fiber network caused by an imbalance within the lower respiratory tract between elastase(s) and protease inhibitors. This hypothesis is based largely on studies of persons with genetic deficiency of serum alpha 1-proteinase inhibitor. We recently reported a spontaneously occurring emphysema in the pallid mouse with an inherited deficiency of serum alpha 1-proteinase inhibitor. This animal reproduces important features of the human condition. We describe here the changes in alveolar elastolytic burden and in the bronchoalveolar lavage (BAL) cell population, which precede and accompany the development of emphysema in pallid mice.
A possible correlation between the levels of lung elastase burden and the loss of lung elastin content was investigated in the period of development of emphysema in pallid mice. Changes in alveolar cells were investigated for specimens from BAL fluids and lung tissue by cytologic, histologic, and immunogold-electron microscopic methods.
An immunogold-positive reaction for elastase was observed on elastin within the alveolar walls of pallid mice from 2 months onward. The average of gold particle density progressively increased with age, reaching high values at 12 and 16 months of age, the age at which parenchymal destruction was previously reported to occur. Lung elastin content had normal values at 2, 4, and 8 months of age. However, it was significantly lower at 12 and 16 months of age. The immunogold values of elastase burden correlated inversely with the decrease in lung elastin content. Total and differential cell counts from BAL fluids of pallid mice did not differ significantly at any time in life and were similar to age-matched controls. However, in pallid mice from 8 months of life onward, pulmonary macrophages contained characteristic intracytoplasmic crystalloid inclusions, which were electrondense and bounded by a single membrane. Using electron microscopy and an immunogold-labeling technique with anti-mouse I-III collagen IgG, these inclusions were identified as collagen-derived products.
The data reported in this paper suggest that emphysematous lesions in pallid mice are associated with a progressive increase of elastase in alveolar intestitium and with loss of lung elastin. Surprisingly, the number of neutrophils in BAL fluids does not increase with the increase of lung elastolytic burden. However, intracytoplasmic crystalloid inclusions related to collagen degradation were observed in pulmonary macrophages of pallid mice at the time of septal disruption. The presence of similar structures in alveolar macrophages from mice or other animal species may be indicative of connective tissue breakdown or remodeling of tissue collagen.
根据当前的一种假说，肺气肿是由下呼吸道内弹性蛋白酶和蛋白酶抑制剂之间的失衡导致弹性纤维网络受损所致。这一假说很大程度上基于对血清α1-蛋白酶抑制剂基因缺陷患者的研究。我们最近报道了一种苍白小鼠自发性肺气肿，其血清α1-蛋白酶抑制剂存在遗传性缺陷。这种动物再现了人类疾病的重要特征。我们在此描述了苍白小鼠肺气肿发生之前及伴随过程中肺泡弹性溶解负荷和支气管肺泡灌洗（BAL）细胞群的变化。
在苍白小鼠肺气肿发展期间，研究了肺弹性蛋白酶负荷水平与肺弹性蛋白含量损失之间可能的相关性。通过细胞学、组织学和免疫金电子显微镜方法，对BAL液和肺组织标本中的肺泡细胞变化进行了研究。
从2个月起，在苍白小鼠肺泡壁的弹性蛋白上观察到弹性蛋白酶的免疫金阳性反应。金颗粒密度的平均值随年龄逐渐增加，在12个月和16个月时达到高值，此前报道此时会发生实质破坏。肺弹性蛋白含量在2、4和8个月龄时正常。然而，在12个月和16个月龄时显著降低。弹性蛋白酶负荷的免疫金值与肺弹性蛋白含量的降低呈负相关。苍白小鼠BAL液中的总细胞计数和分类细胞计数在生命中的任何时候都没有显著差异，且与年龄匹配的对照组相似。然而，从8个月龄起，苍白小鼠的肺巨噬细胞含有特征性的胞浆内晶体包涵体，这些包涵体电子致密，由单层膜包被。使用电子显微镜和抗小鼠I-III型胶原IgG的免疫金标记技术，这些包涵体被鉴定为胶原衍生产物。
本文报道的数据表明，苍白小鼠的肺气肿病变与肺泡间质中弹性蛋白酶的逐渐增加以及肺弹性蛋白的损失有关。令人惊讶的是，BAL液中中性粒细胞的数量并未随着肺弹性溶解负荷的增加而增加。然而，在间隔破坏时，在苍白小鼠的肺巨噬细胞中观察到与胶原降解相关的胞浆内晶体包涵体。在小鼠或其他动物物种的肺泡巨噬细胞中存在类似结构可能表明结缔组织分解或组织胶原重塑。
