Alveolar epithelial inter-alpha-trypsin inhibitor heavy chain 4 deficiency associated with senescence-regulated apoptosis by air pollution

Chen, Xiao Yue; Feng, Po Hao; Han, Chia Li; Jheng, Yu; Wu, Chih Da; Chou, Hsiu Chu; Chen, Yiying; Wu, Sheng; Lee, Kang Yun; Kuo, Han Pin; Chung, Kian Fan; Hsiao, Tzu-Chien; Chen, Kuan Yuan; Ho, Shu-Chuan; Chang, Ta Yuan; Chuang, Hsiao Chi

doi:10.1016/j.envpol.2021.116863

Cited by 16 publications

(10 citation statements)

References 26 publications

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“…The inflammation‐regulating role of ITIH4 is conflicting; although some studies showed that ITIH4 served as a pro‐inflammatory cytokine, several evidence has disclosed the anti‐inflammatory properties of ITIH4 in COPD, inflammatory bowel disease, etc. 24 , 39 , 40 , 41 For instance, one previous study finds that ITIH4 is negatively related to IL‐6 in bronchoalveolar lavage fluid of COPD patients. 39 Another study discovers that ITIH4 knockdown induces TNF‐α, IL‐1β, and IL‐6 expression in human placental choriocarcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

“… 24 , 39 , 40 , 41 For instance, one previous study finds that ITIH4 is negatively related to IL‐6 in bronchoalveolar lavage fluid of COPD patients. 39 Another study discovers that ITIH4 knockdown induces TNF‐α, IL‐1β, and IL‐6 expression in human placental choriocarcinoma cells. 40 However, no clinical study explores the correlation of ITIH4 with inflammatory cytokines and disease activity of RA patients.…”

Section: Discussionmentioning

confidence: 99%

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Inter‐alpha‐trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis

2022

Clinical Laboratory Analysis

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Objective Inter‐alpha‐trypsin inhibitor heavy chain 4 (ITIH4) regulates immunity and inflammation, but its clinical role in rheumatoid arthritis (RA) patients remains unclear. Hence, this study was conducted to explore the association of circulating ITIH4 with disease risk, clinical features, inflammatory cytokines, and treatment outcomes of RA. Methods After the enrollment of 93 active RA patients and 50 health controls (HCs), their serum ITIH4 level was analyzed by enzyme‐linked immunosorbent assay (ELISA). For RA patients only, serum ITIH4 level at week (W) 6 and W12 after treatment was also analyzed. Besides, serum tumor necrosis factor‐alpha (TNF‐α), interleukin (IL)‐1β, IL‐6, and IL‐17A at baseline of RA patients were also detected by ELISA. Results ITIH4 was downregulated in RA patients (151.1 (interquartile range (IQR): 106.2–213.5) ng/mL) than in HCs (306.8 (IQR: 238.9–435.1) ng/mL) (p < 0.001). Furthermore, ITIH4 was negatively related to C‐reactive protein (CRP) (rs = −0.358, p < 0.001) and 28‐joint disease activity score using erythrocyte sedimentation rate (DAS28‐ESR) (rs = −0.253, p = 0.014) in RA patients, but not correlated with other clinical features (all p > 0.05). Besides, ITIH4 was negatively linked with TNF‐α (rs = −0.337, p = 0.001), IL‐6 (rs = −0.221, p = 0.033), and IL‐17A (rs = −0.368, p < 0.001) in RA patients, but not correlated with IL‐1β (rs = −0.195, p = 0.061). Moreover, ITIH4 was gradually elevated in RA patients from baseline to W12 after treatment (p < 0.001). Additionally, the increment of ITIH4 at W6 and W12 was linked with treatment response and remission in RA patients (all p < 0.05). Conclusion Circulating ITIH4 possesses clinical utility in monitoring disease risk, inflammation, disease activity, and treatment outcomes of RA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inter‐alpha‐trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis

2022

Clinical Laboratory Analysis

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“…Meanwhile, the current study also disclosed that serum ITIH4 at any time point declined in sepsis deaths compared to survivors. The potential reasons would be that: (1) ITIH4 exerted an anti‐inflammatory effect; thus, its decrease could reflect aggravated inflammation 13,14 ; (2) ITIH4 involved in the pathology of multiorgan function and its reduction might represent anabatic lung and kidney injury 33–35 . Notably, inflammation and multiorgan injuries were worse in sepsis deaths compared with survivors 37 ; thus, serum ITIH4 at any time point was reduced in deaths in contrast to survivors.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal change of serum inter‐alpha‐trypsin inhibitor heavy chain H4, and its correlation with inflammation, multiorgan injury, and death risk in sepsis

Zhao

Guo²,

et al. 2023

Clinical Laboratory Analysis

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Background: Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) inhibits infectioninduced inflammation and multiorgan injury through several methods. The present study aimed to estimate the association of serum ITIH4 with inflammatory cytokines, multiorgan injury, and death risk in sepsis patients.Methods: Serum samples were collected to detect ITIH4 by enzyme-linked immunosorbent assay in 127 sepsis patients at admission (baseline), day (D)1, D3, and D7 after admission, as well as in 30 healthy controls (HCs). Additionally, 28-day mortality was recorded in sepsis patients. Results: ITIH4 was reduced in sepsis patients versus HCs (median [interquartile

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“…Hyzdalova et al found that two-week exposure of A549 to benzo[α]pyrene (B[a]P) signi cantly inhibited cell proliferation, induced increased number of senescent cells, and promoted p21dependent epithelial-to-mesenchymal transition (EMT)-like phenotype [28]. Chen et al also found that when exposure to diesel exhaust particles (DEPs), the reduced expression of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) as a type II acute-phase protein could be a vital reason for the senescence of alveolar epithelial (A549) cells [29]. Here, it was indicated that PM 2.5 induced the senescence-like phenotype of A549 cells in a time-and concentration-dependent manner, as evidenced by the cell cycle arrest in G2/M phase, the elevated protein level of p16 and p21, the increased percentage of SA-β-galpositive cells (Figs.…”

Section: Discussionmentioning

confidence: 99%

Selenomethionine mitigate PM2.5-induced senescence of alveolar epithelial cells via attenuating inflammatory response mediated by cGAS/STING/NF-κB pathway

Wang

Xia

et al. 2022

Preprint

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Particulate matter 2.5 (PM2.5) is a widely known atmospheric pollutant which could induce the aging-related pulmonary diseases such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and interstitial pulmonary fibrosis (IPF). In recent years, with the increasing atmospheric pollution, airborne fine PM2.5, which is an integral part of air pollutants, has become a thorny problem. Hence, this study focused on the effect of PM2.5 on the senescence of pulmonary epithelial (A549) cells, identifying which inflammatory pathway mediated PM2.5-induced cellular senescence and how to play a protective role against this issue. Our data suggested that PM2.5 induced time- and concentration-dependent increasement in the senescence of pulmonary epithelial cells. Using a inhibitor of cGAS (PF-06928215) and a inhibitor of NF-κB (BAY 11-7082), it was revealed that PM2.5-induced senescence was regulated by inflammatory response, which was closely related to the cGAS/STING/NF-κB pathway activated by DNA damage. Moreover, our study also showed that when A549 cells were exposed to 100 µg/mL PM2.5 for 48 h, the pretreatment with 20 µM selenomethionine (Se-Met) for 12 h could inhibit inflammatory response and prevent cellular senescence by hindering cGAS/STING/NF-κB pathway. These findings indicated that selenium made a defense capability for PM2.5-induced senescence of alveolar epithelial cells, which provided a novel insight for resisting the harm of PM2.5 to human health.

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Alveolar epithelial inter-alpha-trypsin inhibitor heavy chain 4 deficiency associated with senescence-regulated apoptosis by air pollution

Cited by 16 publications

References 26 publications

Inter‐alpha‐trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis

Inter‐alpha‐trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis

Longitudinal change of serum inter‐alpha‐trypsin inhibitor heavy chain H4, and its correlation with inflammation, multiorgan injury, and death risk in sepsis

Selenomethionine mitigate PM2.5-induced senescence of alveolar epithelial cells via attenuating inflammatory response mediated by cGAS/STING/NF-κB pathway

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