微塑料负荷诱导炎症反应参与肺动脉高压的研究进展

Research progress on microplastic load‑induced inflammatory response in pulmonary hypertension

摘要

肺动脉高压是一类以肺血管阻力、肺动脉压力进行性增高为特征的疾病，目前肺动脉高压的发病机制尚不明确，药物治疗主要以扩张肺血管为主。微塑料作为一种环境中广泛存在的污染物，可通过消化、呼吸和皮肤接触途径进入人体，在氧化应激、炎症、细胞死亡等方面影响人体健康，本文简要综述了微塑料、炎症与肺动脉高压之间可能的关联。

Abstract

Pulmonary hypertension (PH) is a group of diseases characterized by progressive increase in pulmonary vascular resistance and pulmonary artery pressure. The pathogenesis of PH remains unclear, and pharmacological treatment primarily focuses on pulmonary vasodilation. Microplastics, as ubiquitous environmental pollutants, can enter the human body through ingestion, inhalation, and skin contact, exerting adverse health effects through mechanisms including oxidative stress, inflammation, and cell death. This review briefly explores the potential involvement of microplastics and inflammation in the pathogenesis of pulmonary hypertension.

关键词

肺动脉高压 / 微塑料 / 炎症 / 氧化应激

Key words

Pulmonary Hypertension / Microplastics / Inflammation / Oxidative Stress

肺动脉高压（pulmonary hypertension，PH）是一组以肺血管阻力进行性升高、肺动脉压力异常增高为血流动力学特征的临床综合征，可导致右心衰竭甚至死亡。其中，动脉型肺动脉高压（pulmonary arterial hypertension，PAH）为首要亚型^［1］。儿童PAH疾病谱以遗传性、发育性疾病为主^［2］。既往研究^［3］认为，PAH血管异常发生可能与胎儿期及围产期肺血管发育不良有关。

肺动脉高压的发病机制目前尚不明确，一氧化氮、前列环素及神经体液和激素通路等各种信号通路之间复杂交错，线粒体相关代谢环境失调，以及环境和炎症损伤等都参与其中^［4］。肺血管重构可能是遗传、氧化应激、免疫、炎症等共同作用的结果^［5］。微塑料（microplastics，MPs）是一种新型污染物，可经多种途径进入人体。近年来，MPs在呼吸系统疾病中的作用过程取得了迅速的研究进展，暴露（毒性、摄入、积累和代谢）、基因、氧化应激、炎症和细胞死亡是其主要的研究领域^［6］。作为一种外源性炎性物质，MPs进入人体后，可引起氧化应激、炎症、内皮损伤等一系列机体反应。本文简述了MPs、炎症反应与肺动脉高压间的可能关联，以期为肺动脉高压的发病机制及药物研究提供新的思路。

1 微塑料与炎症

1.1　微塑料的分类与分布

2004年，THOMPSON等^［7］将粒径小于5 mm的塑料颗粒定义为MPs。随着检测技术发展，粒径小于1 μm的纳米塑料（nanoplastics，NPs）被检出^［8］。环境中MPs与NPs广泛共存，二者合称微纳米塑料。

MPs在环境中的存在形式主要有微纤维、碎片、微珠和颗粒等，可通过消化、呼吸和皮肤接触途径进入人体^［9］。食品中的MPs来源于食品原料，食品加工过程以及食品塑料包装等^［10］；空气中的MPs主要来自悬浮灰尘、轮胎磨损以及垃圾焚烧^［11］。MPs的皮肤接触主要来自洗护产品、化妆品和纺织品中的超细纤维^［12］。而粒径在100 nm以下的NPs可以穿透细胞膜、肺泡上皮屏障和肠道屏障，经过血液循环转移到全身各个器官^［13］。研究人员在人类胎盘^［14］、胎粪^［15］、母乳^［16］、血液^［17］、肺^［18］、动脉斑块^［19］等组织中均发现微塑料的存在。

1.2　微塑料与炎症

病原体、诱变剂和异物（包括微纳米塑料）等有害物质可归类为炎症因子，引起细胞应激与组织损伤^［20］。损伤相关分子模式（damage‑associated molecular patterns，DAMPs）是由受损、应激或死亡细胞释放的内源性危险信号分子，可激活免疫应答和炎症信号通路，具有重要调控作用^［21］。

人体经呼吸道吸入MPs后，<1 μm的颗粒可通过布朗运动到达肺泡表面，沉积后的部分MPs通过纤毛黏液运动及肺泡巨噬细胞吞噬等机制被清除^［22］。LU等^［23］的实验表明，MPs暴露可导致小鼠肺部炎症细胞浸润，肺泡灌洗液中肿瘤坏死因子‑α（tumor necrosis factor‑α，TNF‑α）水平显著升高，荧光染色发现巨噬细胞可吞噬MPs。当微纤维长度超过巨噬细胞可吞噬范围时，吞噬作用受阻，进而诱导白细胞介素‑1β（interleukin‑1β，IL‑1β）、IL‑8等促炎因子释放，加剧局部炎症反应^［24］。多项研究^{［19，25‑30］}发现了MPs在炎症、氧化应激、细胞毒性等方面对不同细胞系及人体产生的影响（见表1）。

2 肺动脉高压与炎症

肺动脉高压是由多种因素导致的远端肺小动脉改变。炎症细胞浸润血管病变部位，促炎细胞因子和趋化因子的组织/血清浓度升高，均在PAH的发生发展中起着重要作用^［31］。在PAH患者的肺组织中，几乎所有的炎性细胞谱系都在重塑的肺血管附近检测到。在PAH动物模型和PAH患者中证实了各种细胞因子和趋化因子的高表达，并检测到了自身抗体的存在。重要的是，PAH中这种血管周围炎症的浸润程度与肺血管血流动力学、血管重塑和临床结果密切相关^［32］。

肺泡巨噬细胞在受到外源性抗原刺激时，启动DAMPs，通过释放大量炎症介质及蛋白酶等活性物质在组织局部发挥生物学效应^{［33‑34］}。巨噬细胞可分为两种亚型：经典活化M1巨噬细胞和交替活化M2巨噬细胞，受到外源损伤刺激后，首先表现出M1表型，释放IL‑1β、TNF‑α、IL‑6、IL‑12等对抗刺激，如果M1期持续时间长，就会引起组织损伤^［35］。因此，M2巨噬细胞会分泌高浓度的IL‑10和转化生长因子‑β，以抑制炎症，促进组织修复、重塑、血管生成，并维持内环境稳定^［35］。M1巨噬细胞异常极化增多可导致组织损伤加重、经久不愈，M2巨噬细胞异常极化增多可导致瘢痕形成和血管增生、癌症等不良异常修复过程出现。巨噬细胞M1、M2极化不平衡在PAH进展中起关键作用，其中肺血管周围微环境在巨噬细胞极化中至关重要^［5］。

3 小结

MPs作为一种炎性物质，可经多种途径进入人体，细胞可经胞饮和吞噬两种方式摄入微塑料，进而引发溶酶体受累、氧化应激反应和炎症因子（IL‑8、IL‑1β、TNF‑α、IL‑6等）升高等一系列反应，而肺动脉高压虽然机制不明，但与炎症密切相关。因此，我们推测MPs通过血液循环和呼吸道吸入途径沉积在肺部血管中，可能引起持续性肺血管炎性损伤，导致血管内皮损害，最终血管瘢痕形成、血管狭窄甚至闭塞。目前肺动脉高压的靶向药物治疗主要针对的是舒张肺动脉，虽然在一定程度上能延缓病程，但无法逆转肺血管重构的病理过程，无法阻止疾病的进展。对于药物难治性肺动脉高压患者来说，经皮降主动脉‑左肺动脉支架植入（Potts分流术）可一定程度提高患者运动能力，改善临床症状，保护右心功能；但若已经处于右心功能衰竭终末期，房间隔造口术则是另一种姑息治疗方法，肺移植仍是最终治疗手段。MPs作为肺动脉高压的潜在危险因素，其致病机制亟待深入阐明。期待未来开展更多MPs暴露与肺动脉高压关联性间的研究，为揭示PH新病因以及药物研发提供新方向。

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