Preferential Macrophage Recruitment and Polarization in LPS-Induced Animal Model for COPD: Noninvasive Tracking Using MRI

Abstract

Noninvasive imaging of macrophages activity has raised increasing interest for diagnosis of chronic obstructive respiratory diseases (COPD), which make them attractive vehicles to deliver contrast agents for diagnostic or drugs for therapeutic purposes. This study was designed to monitor and evaluate the migration of differently polarized M1 and M2 iron labeled macrophage subsets to the lung of a LPS-induced COPD animal model and to assess their polarization state once they have reached the inflammatory sites in the lung after intravenous injection. Ex vivo polarized bone marrow derived M1 or M2 macrophages were first efficiently and safely labeled with amine-modified PEGylated dextran-coated SPIO nanoparticles and without altering their polarization profile. Their biodistribution in abdominal organs and their homing to the site of inflammation in the lung was tracked for the first time using a free-breathing non-invasive MR imaging protocol on a 4.7T magnet after their intravenous administration. This imaging protocol was optimized to allow both detection of iron labeled macrophages and visualization of inflammation in the lung. M1 and M2 macrophages were successfully detected in the lung starting from 2 hours post injection with no variation in their migration profile. Quantification of cytokines release, analysis of surface membrane expression using flow cytometry and immunohistochemistry investigations confirmed the successful recruitment of injected iron labeled macrophages in the lung of COPD mice and revealed that even with a continuum switch in the polarization profile of M1 and M2 macrophages during the time course of inflammation a balanced number of macrophage subsets predominate.

Experimental animal models for COPD: a methodological review

“…Increased BAL inflammatory cytokine secretion such as keratinocyte chemoattractant (KC), TNF-α [84], macrophage inflammatory proteins (MIP-2 and MIP-1 α) and MCP-1 were also observed in animal models of CS-induced COPD [22]. Increased levels of ILs (IL-12 and IL-4) and chemokines (CXCL-10 and CCL-22) in BAL of LPS-exposed mice were also reported [79, 80]. …”

Specific targeting and noninvasive magnetic resonance imaging of an asthma biomarker in the lung using polyethylene glycol functionalized magnetic nanocarriers

“…The recent progress in the developments of UTE sequence and high‐performance gradients allowed us to obtain artifact‐free images of the lungs with high spatial resolution and sufficient signal in parenchymal tissues. We and other researchers have applied this novel sequence for enhanced detection of several inflammatory diseases (i.e. COPD, asthma, …) and simultaneous sensitive detection of iron‐oxide‐based nanoparticles in the lung.…”

“…Analyses were performed on BD™ LSR II flow cytometer using DIVA software (BD Biosciences, USA). The dissected lungs were held in complete DMEM medium, minced, and filtered through a gauze cloth as previously described . The filtrates were then centrifuged (1500 rpm for 5 min) and resuspended in PBS, and the viability of cells was determined.…”

Cell Tracking in Cancer Immunotherapy

“…During inflammatory disease such as arthritis, atherosclerotic plaques, in vivo staining of the macrophage with 111 In-or 64 Cu-labeled antibodies allowed imaging follow-up, evaluation of therapeutic efficacy and therapy adaption (98,99). For acute or chronic obstructive pulmonary disease, the recruitment of macrophages was monitored by labeling with amine-modified PEGylated dextran-coated SPIO and MRI (81).…”