Taylor R G, McCall C E, Thrall R S, Woodruff R D, O'Flaherty J T
Lab Invest. 1985 Jan;52(1):61-70.
Rabbits given daily intravenous injections of phorbol myristate acetate (PMA) develop acute and chronic pulmonary disease. We distinguished three phases in the histologic progression of the lung injury. An acute phase (occurring within 1.5 hours of the first injection) involved hemorrhagic pneumonitis, increased lung weight, and increased numbers of neutrophils as well as erythrocytes in alveolar fluid. The intermediate phase (occurring 1 to 7 days after the initial injection) involved interstitial pneumonitis: neutrophils and macrophages infiltrated into lung interstitium and alveolar fluid. The relative number of type II alveolar epithelial cells increased dramatically and lung weight became maximal during this phase. In the chronic phase (occurring within 14 days and lasting greater than 77 days) diffuse interstitial fibrosis progressed, whereas inflammatory changes abated. Animals treated daily with PMA developed a linear increase in lung hydroxyproline content beginning on the 7th day of treatment. Values increased to three to four times above controls by day 77. Animals treated with PMA for only 14 days and sacrificed up to 63 days thereafter had lung hydroxyproline values that were intermediate between controls and animals injected daily for 77 days. Their fibrosis neither progressed nor reversed when PMA treatment was stopped. In contrast, animals receiving a single dose of PMA developed only the acute and intermediate phases of injury; no detectable fibrosis occurred, and their lung reactions resolved completely. Finally, animals made neutropenic with nitrogen mustard did not respond to PMA with increased lung weight or changes in alveolar lavage fluid cellularity during the early or intermediate phases of the disease. They did, however, exhibit increased interstitial cellularity. Thus, PMA produces abrupt pneumonitis that progresses to fibrosis. The acute and intermediate phases of injury are neutrophil dependent and reversible, whereas the chronic fibrotic phase is irreversible and requires continued PMA injections for progression.
每日静脉注射佛波酯（PMA）的兔子会患上急性和慢性肺部疾病。我们在肺损伤的组织学进展中区分出三个阶段。急性期（在首次注射后1.5小时内出现）包括出血性肺炎、肺重量增加以及肺泡液中中性粒细胞和红细胞数量增多。中间期（在初次注射后1至7天出现）包括间质性肺炎：中性粒细胞和巨噬细胞浸润到肺间质和肺泡液中。在此阶段，II型肺泡上皮细胞的相对数量急剧增加，肺重量达到最大值。在慢性期（在14天内出现并持续超过77天），弥漫性间质纤维化进展，而炎症变化减轻。每日用PMA治疗的动物从治疗第7天开始肺羟脯氨酸含量呈线性增加。到第77天时，其值比对照组增加了三到四倍。仅用PMA治疗14天并在之后长达63天处死的动物，其肺羟脯氨酸值介于对照组和每日注射77天的动物之间。当停止PMA治疗时，它们的纤维化既不进展也不逆转。相比之下，接受单次剂量PMA的动物仅出现损伤的急性和中间阶段；未检测到纤维化，并且它们的肺部反应完全消退。最后，用氮芥使中性粒细胞减少的动物在疾病的早期或中间阶段对PMA没有出现肺重量增加或肺泡灌洗液体细胞成分变化的反应。然而，它们确实表现出间质细胞增多。因此，PMA会引发急性肺炎并进展为纤维化。损伤的急性和中间阶段依赖中性粒细胞且是可逆的，而慢性纤维化阶段是不可逆的，并且需要持续注射PMA才能进展。
