Molecular imaging of fibrosis: recent advances and future directions

Abstract

Fibrosis, the progressive accumulation of connective tissue that occurs in response to injury, causes irreparable organ damage and may result in organ failure. The few available antifibrotic treatments modify the rate of fibrosis progression, but there are no available treatments to reverse established fibrosis. Thus, more effective therapies are urgently needed. Molecular imaging is a promising biomedical methodology that enables noninvasive visualization of cellular and subcellular processes. It provides a unique means to monitor and quantify dysregulated molecular fibrotic pathways in a noninvasive manner. Molecular imaging could be used for early detection, disease staging, and prognostication, as well as for assessing disease activity and treatment response. As fibrotic diseases are often molecularly heterogeneous, molecular imaging of a specific pathway could be used for patient stratification and cohort enrichment with the goal of improving clinical trial design and feasibility and increasing the ability to detect a definitive outcome for new therapies. Here we review currently available molecular imaging probes for detecting fibrosis and fibrogenesis, the active formation of new fibrous tissue, and their application to models of fibrosis across organ systems and fibrotic processes. We provide our opinion as to the potential roles of molecular imaging in human fibrotic diseases.

Figure 1. Conceptual applications of molecular imaging in human fibrotic diseases.

(A) Target engagement. PET imaging in an early stage clinical trial for a novel antifibrotic therapy. PET ligand binds to the molecular target of Drug A. Modeling the Drug A dose-dependent change in PET signal provides target concentration and affinity of Drug A for the target. (B) Target expression. PET imaging with a molecular probe that binds to a molecular target implicated in pulmonary fibrosis pathogenesis. PET imaging differentiates high versus low expression of the molecular target, selecting patients for treatment with an inhibitor of the molecular target. (C) Diagnosis and staging. Patients at risk for liver fibrosis undergo conventional liver MRI and liver MRI with a molecular probe. Degree of MRI signal enhancement enables earlier detection of fibrosis and noninvasive determination of disease stage. (D) Cohort enrichment for clinical trials. PET imaging with a molecular probe performed on IPF subjects for noninvasive detection of disease activity. Conventional CT demonstrates degree of fibrosis but does not inform as to disease activity. PET signal uptake differentiates subjects by degree of disease activity. This information can be utilized in clinical trials to enrich for subjects most likely to meet prespecified primary endpoints. (E) Treatment response. Subjects with cardiac fibrosis undergo treatment with a novel therapy that reverses fibrosis. MRI using a fibrosis-specific Gd probe detects regression in fibrosis earlier than late gadolinium-enhanced MRI. Note: these are hypothetical scenarios that have not yet been performed in humans.

Figure 2. Schematic representation of wound-healing responses resulting in fibrosis.

(A) Tissue injury occurs, resulting in cell death and influx of immune cells. Resident and recruited macrophages migrate to the area of injury. (B) Tissue injury also results in increased endothelial permeability (i.e., vascular leak), and activation of the coagulation cascade with formation of a fibrin clot. (C) Fibroblasts migrate to the area of injury. (D) Recruited fibroblasts become activated and differentiate into myofibroblasts. (E) Formation of a provisional extracellular matrix develops and cross-linking occurs. In the setting of normal wound healing, tissue regeneration occurs. During fibrosis, excessive matrix accumulation occurs instead, resulting in organ damage. Available molecular probes are noted by the specific wound-healing response they target or for LPA and αvβ6, the wound-healing responses they activate. Some probes target or activate more than one wound-healing process. Adapted with permission from the American Journal of Respiratory and Critical Care Medicine (ref. 12), copyright 2018, American Thoracic Society.