Pathology, toxicology, and latency of irritant gases known to cause bronchiolitis obliterans disease: Does diacetyl fit the pattern?
Pathology, toxicology, and latency of irritant gases known to cause bronchiolitis obliterans disease: Does diacetyl fit the pattern?
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DOI：
10.1016/j.toxrep.2015.10.012
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发表时间：
2015
影响因子：
--
通讯作者：
Fedoruk MJ
中科院分区：
文献类型：
--
作者：
Kerger BD;Fedoruk MJ
闭塞性细支气管炎（BO）是一种罕见的疾病，涉及同心细支气管纤维化，在吸入足够高的急性剂量的某些刺激性气体后迅速发展。虽然在各种慢性肺部疾病中有许多涉及细支气管病变的潜在原因，但未能明确定义临床特征和病理特征可能导致诊断不明确。已知引起BO的刺激性气体遵循类似的病理过程和人类疾病发作的时间过程。对已知引起BO的吸入刺激性气体的研究（例如，氯、盐酸、氨、氮的氧化物、硫的氧化物、硫或氮的汞和光气）表明，在因果化学品暴露和临床上显著的BO疾病的发展之间的时间过程通常限于几个月。这些刺激性气体产生毒性作用的机制通常涉及细支气管上皮衬里的广泛和严重损伤，导致急性呼吸道症状，包括数天内的肺水肿。反复暴露于浓度不足以引起明显呼吸窘迫或水肿的吸入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变化。刺激性气体引起BO的风险主要是由毒代动力学影响细支气管上皮细胞的浓度引起的。引起BO（如氨）的高度可溶性刺激性气体通常遵循阈值依赖性细胞毒性作用机制，在足够高的剂量下，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、肺水肿和炎后同心纤维化，在几个月内临床上变得明显。相比之下，具有较低溶解度的刺激性气体（如光气）也遵循细胞毒性作用的阈值依赖性机制，但可表现出更隐蔽和孤立的细支气管组织损伤，具有类似的纤维化潜伏期。迄今为止，对高度可溶性气体双乙酰的动物和人类研究尚未确定基于闭塞性细支气管炎疾病的其他已知原因的研究所预期的病理学和潜伏期的一致模式。
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.