Early Detection and Staging of Lung Fibrosis Enabled by Collagen-Targeted MRI Protein Contrast Agent.

• Type of Material: Article
• Authors: Oluwatosin Y Ibhagui, Georgia State University, Atlanta; Dongjun Li, Georgia State University, Atlanta; Honhwei Han, Georgia State University, Atlanta; Guangda Peng, Georgia State University, Atlanta; Maureen L Meister, Georgia State University, Atlanta; Zongxiang Gui, Georgia State University, Atlanta; Jingjuan Qiao, Georgia State University, Atlanta; Mani Salarian, Georgia State University, Atlanta; Bin Dong, Georgia State University, Atlanta; Yi Yuan, Georgia State University, Atlanta; Yiting Xu, Georgia State University, Atlanta; Hua Yang, Emory University; Shanshan Tan, Georgia State University, Atlanta; Ganesh Satyanarayana, Georgia State University, Atlanta; Shenghui Xue, InLighta Biosciences, Atlanta, Georgia 30303, United States.; Ravi Chakra Turaga, Georgia State University, Atlanta; Malvika Sharma, Georgia State University, Atlanta; Yan Hai, Georgia State University, Atlanta; Yuguang Meng, Emory University; Khan Hekmatyar, Georgia State University, Atlanta; Phillip Zhe Sun, Emory University; Gabriel Sica, Emory University; Xiangming Ji, Georgia State University, Atlanta; Zhi-ren Liu, Georgia State University, Atlanta; Jenny J Yang, Georgia State University
• Language: English
• Date: 2023-06-26
• Publisher: Nanjing University and American Chemical Society
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Co-published by Nanjing University and American Chemical Society
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1021/cbmi.3c00023
• Title of Journal or Parent Work: Chem Biomed Eng
• Volume: 1
• Issue: 3
• Start Page: 268
• End Page: 285
• Grant/Funding Information: This work was supported in part by NIH grants R33CA235319, R42AA112713, R42CA183376, and S10OD027045 to J.J.Y. This work was also supported by FAMRI foundation YFEL141014 to X.J., and Georgia State University CDT fellowships to Z.G. and O.I., and MBD fellowship to D.L.
• Keywords: heterogeneity; IPF; COPD; fibrosis; collagen; MRI; lung disease; early detection
• Research Categories: Health Sciences, Opthamology; Health Sciences, Medicine and Surgery

Abstract

Chronic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), are major leading causes of death worldwide and are generally associated with poor prognoses. The heterogeneous distribution of collagen, mainly type I collagen associated with excessive collagen deposition, plays a pivotal role in the progressive remodeling of the lung parenchyma to chronic exertional dyspnea for both IPF and COPD. To address the pressing need for noninvasive early diagnosis and drug treatment monitoring of pulmonary fibrosis, we report the development of human collagen-targeted protein MRI contrast agent (hProCA32.collagen) to specifically bind to collagen I overexpressed in multiple lung diseases. When compared to clinically approved Gd3+ contrast agents, hProCA32.collagen exhibits significantly better r1 and r2 relaxivity values, strong metal binding affinity and selectivity, and transmetalation resistance. Here, we report the robust detection of early and late-stage lung fibrosis with stage-dependent MRI signal-to-noise ratio (SNR) increase, with good sensitivity and specificity, using a progressive bleomycin-induced IPF mouse model. Spatial heterogeneous mapping of usual interstitial pneumonia (UIP) patterns with key features closely mimicking human IPF, including cystic clustering, honeycombing, and traction bronchiectasis, were noninvasively detected by multiple MR imaging techniques and verified by histological correlation. We further report the detection of fibrosis in the lung airway of an electronic cigarette-induced COPD mouse model, using hProCA32.collagen-enabled precision MRI (pMRI), and validated by histological analysis. The developed hProCA32.collagen is expected to have strong translational potential for the noninvasive detection and staging of lung diseases, and facilitating effective treatment to halt further chronic lung disease progression.