Kerger Brent D, Fedoruk M Joseph
Exponent, Inc., Irvine, CA, USA.
Toxicol Rep. 2015 Nov 2;2:1463-1472. doi: 10.1016/j.toxrep.2015.10.012. eCollection 2015.
Bronchiolitis obliterans (BO) is a rare disease involving concentric bronchiolar fibrosis that develops rapidly following inhalation of certain irritant gases at sufficiently high acute doses. While there are many potential causes of bronchiolar lesions involved in a variety of chronic lung diseases, failure to clearly define the clinical features and pathological characteristics can lead to ambiguous diagnoses. Irritant gases known to cause BO follow a similar pathologic process and time course of disease onset in humans. Studies of inhaled irritant gases known to cause BO (e.g., chlorine, hydrochloric acid, ammonia, nitrogen oxides, sulfur oxides, sulfur or nitrogen mustards, and phosgene) indicate that the time course between causal chemical exposures and development of clinically significant BO disease is typically limited to a few months. The mechanism of toxic action exerted by these irritant gases generally involves widespread and severe injury of the epithelial lining of the bronchioles that leads to acute respiratory symptoms which can include lung edema within days. Repeated exposures to inhaled irritant gases at concentrations insufficient to cause marked respiratory distress or edema may lead to adaptive responses that can reduce or prevent severe bronchiolar fibrotic changes. Risk of BO from irritant gases is driven substantially by toxicokinetics affecting concentrations occurring at the bronchiolar epithelium. Highly soluble irritant gases that cause BO like ammonia generally follow a threshold-dependent cytotoxic mechanism of action that at sufficiently high doses results in severe inflammation of the upper respiratory tract and the bronchiolar epithelium concurrently. This is followed by acute respiratory distress, pulmonary edema, and post inflammatory concentric fibrosis that become clinically obvious within a few months. In contrast, irritant gases with lower solubility like phosgene also follow a threshold-dependent mechanism of cytotoxicity action but can exhibit more insidious and isolated bronchiolar tissue damage with a similar latency to fibrosis. To date, animal and human studies on the highly soluble gas, diacetyl, have not identified a coherent pattern of pathology and latency that would be expected based on studies of other known causes of bronchiolitis obliterans disease.
闭塞性细支气管炎（BO）是一种罕见疾病，涉及同心性细支气管纤维化，在吸入足够高急性剂量的某些刺激性气体后迅速发展。虽然多种慢性肺病中涉及细支气管病变有许多潜在原因，但未能明确界定临床特征和病理特征可能导致诊断不明确。已知可导致BO的刺激性气体在人类中遵循相似的病理过程和疾病发作时间进程。对已知可导致BO的吸入性刺激性气体（如氯、盐酸、氨、氮氧化物、硫氧化物、硫或氮芥子气以及光气）的研究表明，从接触致病化学物质到出现具有临床意义的BO疾病之间的时间进程通常限于几个月。这些刺激性气体发挥的毒性作用机制一般涉及细支气管上皮衬里的广泛严重损伤，导致急性呼吸道症状，可能在数天内出现肺水肿。反复接触浓度不足以引起明显呼吸窘迫或水肿的吸入性刺激性气体可能导致适应性反应，从而减少或预防严重的细支气管纤维化改变。刺激性气体导致BO的风险在很大程度上由影响细支气管上皮细胞浓度的毒物动力学驱动。像氨这样可导致BO的高溶解性刺激性气体通常遵循阈值依赖性细胞毒性作用机制，在足够高剂量时会同时导致上呼吸道和细支气管上皮的严重炎症。随后是急性呼吸窘迫、肺水肿以及炎症后同心性纤维化，在几个月内变得临床上明显。相比之下，像光气这样低溶解性的刺激性气体也遵循阈值依赖性细胞毒性作用机制，但可能表现出更隐匿且孤立的细支气管组织损伤，纤维化潜伏期相似。迄今为止，关于高溶解性气体双乙酰的动物和人体研究尚未发现基于闭塞性细支气管炎疾病其他已知病因研究预期的连贯病理模式和潜伏期。
