ITIH4 attenuates acute lung injury by Fe-containing particulate matter in mice via Hippo pathway in type II alveolar epithelial cells.

IF 5.8 2区医学 Q1 Medicine

Respiratory Research Pub Date : 2025-05-28 DOI:10.1186/s12931-025-03256-z

Vincent Laiman, Syue-Wei Peng, Lina Choridah, Didik Setyo Heriyanto, Fara Silvia Yuliani, Kang-Yun Lee, Ching-Huang Lai, Jer-Hwa Chang, Yueh-Lun Lee, Shu-Chuan Ho, Sheng-Ming Wu, Chia-Li Han, Cheng-Wei Lin, Kian Fan Chung, Hsiao-Chi Chuang

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引用次数: 0

Abstract

Background: Metals in particulate matter (PM), like iron (Fe), were associated with lung injury. Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) was suggested to inhibit lung inflammation. However, the effect of metals in PM, particularly Fe, on lung inflammation involving ITIH4 remained unclear.

Methods: We investigated the effects of recombinant ITIH4 (rITIH4) against acute lung injury in C57BL/6JNarl and B6.Sftpc-CreER^T2;Ai14(RCL-tdT)-D mice exposed to Fe-containing PM. Mice were exposed to diesel exhaust particles (DEP) or soluble iron (FeCl₃) via intratracheal instillation, while rITIH4 treatment was administered intranasally after exposure. Lung function, Fe levels (both bulk and single-cell by inductively-coupled plasma mass spectrometry (ICP-MS) and single-cell ICP-MS, respectively), inflammatory cell infiltration, and Hippo pathway regulation in type II alveolar epithelial cells (AECII) were assessed.

Results: We observed correlation between lung function changes and Fe levels, both in bulk and single-cell Fe in peripheral blood mononuclear cells. Single-cell RNA sequencing of the control group identified AECII-related cells characterized by high Sftpc, Sftpa1, Mzb1, B3 gnt5, Cacna1e, and Agbl1 expression. rITIH4 treatment in DEP-exposed mice restored Hippo pathway Cdh1, Itih4, Pdpn, Wwtr1, and Yap1 in AECII. rITIH4 reversed DEP- and Fe-induced increases in neutrophil infiltration, neutrophil-to-lymphocyte ratio, and monocyte depletion in bronchoalveolar lavage fluid (BALF). rITIH4 reduced BALF CXCL1/KC levels by DEP and serum 8-isoprostane levels by Fe. rITIH4 also reduced DEP-induced lung damage, increased ⍺-catenin and p-YAP in Fe-exposed mice, and pTAZ/TAZ ratio in both DEP- and Fe-exposed mice. rITIH4 increased pYAP/YAP ratio in DEP-exposed mice while decreasing LC3BII/I ratio in Fe-exposed mice.

Conclusion: ITIH4 attenuated acute lung injury in mice exposed to PM, specifically Fe, by modulating the Hippo pathway in AECII.

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ITIH4通过II型肺泡上皮细胞的Hippo通路减轻小鼠含铁颗粒物急性肺损伤。

背景：颗粒物质（PM）中的金属，如铁（Fe），与肺损伤有关。胰蛋白酶间抑制剂重链H4 （ITIH4）可抑制肺部炎症。然而，PM中的金属，特别是铁，对涉及ITIH4的肺部炎症的影响尚不清楚。方法：研究重组ITIH4 （rITIH4）对暴露于含铁PM的C57BL/6JNarl和b6小鼠急性肺损伤的影响。小鼠通过气管内注射暴露于柴油废气颗粒（DEP）或可溶性铁（FeCl₃），而暴露后通过鼻内给予rITIH4治疗。评估II型肺泡上皮细胞（AECII）的肺功能、铁水平（分别通过诱导耦合等离子体质谱（ICP-MS）和单细胞ICP-MS检测）、炎症细胞浸润和Hippo通路调节。结果：我们观察到肺功能的变化与铁水平的相关性，无论是大细胞铁还是外周血单个核细胞铁。对照组单细胞RNA测序发现aecii相关细胞Sftpc、Sftpa1、Mzb1、B3 gnt5、Cacna1e和Agbl1高表达。在暴露于deep的小鼠中，rITIH4处理恢复了AECII中的Hippo通路Cdh1、ih4、Pdpn、Wwtr1和Yap1。rITIH4逆转了DEP和fe诱导的支气管肺泡灌洗液（BALF）中性粒细胞浸润、中性粒细胞与淋巴细胞比值和单核细胞耗损的增加。rITIH4通过DEP降低BALF CXCL1/KC水平，通过Fe降低血清8-异前列腺素水平。rITIH4还能降低DEP诱导的肺损伤，增加fe暴露小鼠的 catenin和p-YAP，以及DEP和fe暴露小鼠的pTAZ/TAZ比值。rITIH4增加了deep暴露小鼠的pYAP/YAP比值，降低了fe暴露小鼠的LC3BII/I比值。结论：ITIH4通过调节AECII中的Hippo通路，减轻PM（特别是Fe）暴露小鼠的急性肺损伤。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Respiratory Research RESPIRATORY SYSTEM-

CiteScore

9.70

自引率

1.70%

发文量

314

审稿时长

4-8 weeks

期刊介绍： Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.