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IGF-1 Receptor Signaling Regulates Type II Pneumocyte Senescence and Resulting Macrophage Polarization in Lung Fibrosis

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Abstract
Purpose: Type II pneumocyte (alveolar epithelial cells type II [AECII]) senescence has been implicated in the progression of lung fibrosis. The capacity of senescent cells to modulate pulmonary macrophages to drive fibrosis is unexplored. Insulin-like growth factor-1 receptor (IGF-1R) signaling has been implicated as a regulator of senescence and aging.

Methods and Materials: Mice with an AECII-specific deletion of IGF-1R received thoracic irradiation (n >= 5 per condition), and the effect of IGF-1R deficiency on radiation-induced AECII senescence and macrophage polarization to an alternatively activated phenotype (M2) was investigated. IGF-1R signaling, macrophage polarization, and senescence were evaluated in surgically resected human lung (n = 63).

Results: IGF-1R deficient mice demonstrated reduced AECII senescence (senescent AECII/field; intact: 7.25% +/- 3.5% [ mean +/- SD], deficient: 2.75% +/- 2.8%, P = .0001), reduced accumulation of M2 macrophages (intact: 24.7 +/- 2.2 cells/field, deficient: 15.5 +/- 1.2 cells/field, P = .0086), and fibrosis (hydroxyproline content; intact: 71.9 +/- 21.7 mu g/lung, deficient: 31.7 +/- 7.9, P = .0485) after irradiation. Senescent AECII enhanced M2 polarization in a paracrine fashion (relative Arg1 mRNA, 0 Gy: 1.0 +/- 0.4, 17.5 Gy: 7.34 +/- 0.5, P < .0001). Evaluation of surgical samples from patients treated with chemoradiation demonstrated increased expression of IGF-1 (unirradiated: 10.2% +/- 4.9% area, irradiated: 15.1% +/- 11.5%, P +/- .0377), p21 (unirradiated: 0.013 +/- 0.02 histoscore, irradiated: 0.084 +/- 0.09 histoscore, P +/- .0002), IL-13 (unirradiated: 13.7% +/- 2.8% area, irradiated: 21.7% +/- 3.8%, P < .0001), and M2 macrophages in fibrotic regions relative to nonfibrotic regions (unirradiated: 11.4 +/- 12.2 CD163 thorn cells/core, irradiated: 43.1 +/- 40.9 cells/core, P = .0011), consistent with findings from animal models of lung fibrosis.

Conclusions: This study demonstrates that senescent AECII are necessary for the progression of pulmonary fibrosis and serve as a targetable, chronic stimuli for macrophage activation in fibrotic lung. Published by Elsevier Inc.
Author(s)
송준선Ayla O. WhiteDeborah E. CitrinDeborah E. CitrinEun Joo ChungIlseon HwangJessica L. ReedyJoon Yong ChungKris YlayaSeokjoo KwonStephen M. Hewitt
Issued Date
2021
Type
Article
Keyword
Alveolar Epithelial Cells - physiologyAlveolar Epithelial Cells - radiation effectsAnalysisAnimalsCarcinomaNon-Small-Cell Lung - pathologyCarcinomaNon-Small-Cell Lung - therapyCell PolarityCellular Senescence - physiologyCellular Senescence - radiation effectsChemoradiotherapyFibrosisGene DeletionGene expressionHumansHydroxyproline - analysisLung - metabolismLung - radiation effectsLung Neoplasms - pathologyLung Neoplasms - therapyMacrophage ActivationMacrophagesMacrophagesAlveolar - physiologyMacrophagesAlveolar - radiation effectsMiceMiceInbred C57BLPulmonary Fibrosis - etiologyPulmonary Fibrosis - pathologyRadiationRadiation InjuriesExperimental - metabolismRadiation InjuriesExperimental - physiopathologyRadiation InjuriesExperimental - prevention &amp; controlReceptorIGF Type 1 - deficiencyReceptorIGF Type 1 - geneticsReceptorIGF Type 1 - metabolismRNA
DOI
10.1016/j.ijrobp.2020.12.035
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8035
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2474843940&amp;context=PC&amp;vid=ULSAN&amp;lang=ko_KR&amp;search_scope=default_scope&amp;adaptor=primo_central_multiple_fe&amp;tab=default_tab&amp;query=any,contains,IGF-1%20Receptor%20Signaling%20Regulates%20Type%20II%20Pneumocyte%20Senescence%20and%20Resulting%20Macrophage%20Polarization%20in%20Lung%20Fibrosis&amp;offset=0&amp;pcAvailability=true
Publisher
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
Location
미국
Language
영어
ISSN
0360-3016
Citation Volume
110
Citation Number
2
Citation Start Page
526
Citation End Page
538
Appears in Collections:
Medicine > Medicine
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