Citrullinated and Malondialdehyde-Acetaldehyde-Modified Fibrinogen Activates Macrophages and Promotes Profibrotic Responses in Human Lung Fibroblasts

Details

• Personal Author:
  Aripova N ; Bailey KL ; Duryee MJ ; England BR ; Hunter CD ; Katafiasz D ; Klingemann LE ; Mikuls TR ; Nelson AJ ; Poole JA ; Thiele GM ; Zhou W
• Description:
  The objective of this study was to assess fibrinogen (FIB) comodified with citrulline (CIT) and/or malondialdehyde-acetaldehyde (MAA) initiates macrophage-fibroblast interactions, leading to extracellular matrix (ECM) deposition that characterizes rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Macrophages (Mo) were stimulated with native-FIB, FIB-CIT, FIB-MAA, or FIB-MAA-CIT. Supernatants (SNs) [Mo-SN (U-937-derived) or MoP-SN (PBMC-derived)] or direct antigens were coincubated with human lung fibroblasts (HLFs). Gene expression was examined using RT-PCR. ECM deposition was quantified using immunohistochemistry and Western blot; cell signaling mechanisms were delineated. Platelet-derived growth factor (PDGF)-BB and TGF-β were measured in macrophage supernatants, and inhibition studies were performed using Su16f and SB431542, respectively. HLF gene expression of CD36, COL6A3, MMP-9, MMP-10, and MMP-12 was increased following stimulations with Mo-SN generated from modified FIB but not from direct antigens. HLF stimulated with MoP-SNFIB-MAA-CIT derived from patients with RA-ILD resulted in 4- to 30-fold increases in COL6A3 and MMP12 expression; upregulation was greater in HLFs stimulated with MoP-SN derived from RA-ILD versus controls. HLF exposure to Mo-SNFIB-MAA-CIT increased types I/VI collagen deposition versus all other Mo-SN groups and was greater than FIB-MAA-CIT stimulation. PDGF-BB and TGF-β signaling had the highest concentrations identified in Mo-SNFIB-MAA-CIT and MoP-SNFIB-MAA-CIT, particularly from RA-ILD-derived cells. PDGF-BB and TGF-β inhibitors, alone and in combination, significantly reduced HLF-mediated ECM deposition from Mo-SN stimulations. These results show that comodified fibrinogen activates macrophages to produce PDGF-BB and TGF-β that promotes an aggressive HLF phenotype characterized by increased ECM deposition. These results suggest that targeting CIT and/or MAA modifications or downstream cellular signals could represent novel approaches to RA-ILD treatment. [Description provided by NIOSH]
• Subjects:
  Antigens Blood Lung Diseases Macrophages Occupational Health Respiratory Tract Diseases Safety
• Keywords:
  Author Keywords: Citrullination Fibroblasts Gene Expression Lung Disease Malondialdehyde-acetaldehyde Platelet Derived Growth Factor Pulmonary Fibrosis Rheumatoid Arthritis Interstitial Lung Disease Rheumatoid Disorders Transforming Growth Factor Beta
• ISSN:
  1040-0605
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Kansas City Region [OSHA] ; Missouri ; Nebraska
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  328
• Issue:
  1
• NIOSHTIC Number:
  nn:20070318
• Citation:
  Am J Physiol Lung Cell Mol Physiol 2025 Jan; 328(1):L134-L147
• Contact Point Address:
  Ted R. Mikuls, M.D, M.S.P.H, Omaha VA/UNMC Experimental18Immunology Laboratory, 986270 Nebraska Medical Center, Omaha, NE 68198-6270
• Email:
  tmikuls@unmc.edu
• CAS Registry Number:
  372-75-8 ; Methylarsonic acid (CAS RN 124-58-3)
• Federal Fiscal Year:
  2025
• Performing Organization:
  University of Nebraska Medical Center
• Peer Reviewed:
  True
• Start Date:
  20210901
• Source Full Name:
  American Journal of Physiology: Lung Cellular and Molecular Physiology
• End Date:
  20250831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:005dbda8ee239e15915ea181452ce078cc5f389bbc9f5b2e5e7cdecc4e64efc6adca1a51ce1d4db5fa80dc72dffb4d83fce31e68df3999b209063ac5a2c0d6b0
• Download URL:
  https://stacks.cdc.gov/view/cdc/208552/cdc_208552_DS1.pdf
• File Type:
  [PDF - 3.00 MB ]