TY - JOUR
T1 - ITIH4 attenuates acute lung injury by Fe-containing particulate matter in mice via Hippo pathway in type II alveolar epithelial cells
AU - Laiman, Vincent
AU - Peng, Syue Wei
AU - Choridah, Lina
AU - Heriyanto, Didik Setyo
AU - Yuliani, Fara Silvia
AU - Lee, Kang Yun
AU - Lai, Ching Huang
AU - Chang, Jer Hwa
AU - Lee, Yueh Lun
AU - Ho, Shu Chuan
AU - Wu, Sheng Ming
AU - Han, Chia Li
AU - Lin, Cheng Wei
AU - Chung, Kian Fan
AU - Chuang, Hsiao Chi
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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-CreERT2;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.
AB - 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-CreERT2;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.
KW - Air pollution
KW - Autophagy
KW - Diesel exhaust particles
KW - Inflammation
KW - Single-cell analysis
UR - https://www.scopus.com/pages/publications/105006762721
UR - https://www.scopus.com/pages/publications/105006762721#tab=citedBy
U2 - 10.1186/s12931-025-03256-z
DO - 10.1186/s12931-025-03256-z
M3 - Article
C2 - 40437524
AN - SCOPUS:105006762721
SN - 1465-9921
VL - 26
JO - Respiratory Research
JF - Respiratory Research
IS - 1
M1 - 201
ER -