Imaging of the human lung - visualizing drug efficacy

Development of an investigational new drug requires the safety and efficacy of the drug candidate to be demonstrated in clinical trials in man. Respiratory diseases such as bronchial asthma and chronic obstructive pulmonary disease (COPD) feature chronic inflammation of the airways. This is why drug development efforts have focused in particular on substances holding promise for an anti-inflammatory effect. The possibility to measure the strength of a drug candidate’s anti-inflammatory action, therefore, is of pivotal importance to enable reliable assessment of its efficacy. In addition, details on the temporal course of action and strength provide valuable information for the evaluation of drug dosage and frequency of administration.

The degree of the inflammation so far has been determined primarily by means of samples from patients’ airways or lungs. To this end, either coughing is induced for sputum collection (induced sputum) or bronchoscopy is performed to collect cells from the lungs by means of brush biopsies or lung lavage. Performance of these examinations can be perfectly safe and they provide important information about cellular composition and cell activation status in the airways and lungs; however, they also put a certain strain on test subjects, so that methods involving no invasive examinations or challenge tests represent a valuable complementary option for efficacy testing of medicinal products.

Magnetic resonance imaging is one such non-invasive method, used to generate images of the human lung. The aim of current research activities is to improve the imaging technology, so as to enable visualization not only of the lung’s structure, but also of inflammatory processes. Airway inflammation involves an influx of liquid into the lung tissue, reduced local ventilation and blood flow, and diminished gas exchange in the lung tissue. By further development of the traditional MRI technology, these processes can be visualized by magnetic resonance imaging. In addition to the classical proton-based sequences, functional examination sequences are used in particular. Furthermore, methods are being developed that enable contrast enhancement in the lungs by means of a gaseous contrast agent, instead of using the traditional proton-based MRI technology.

Recently, we were able to demonstrate that allergen challenge of patients with bronchial asthma induces airway inflammation that can also be visualized by MRI technology. In this study, patients with mild bronchial asthma were challenged by local instillation of allergen during bronchoscopy, a method referred to as segmental allergen challenge, inducing a local inflammatory response in the lung. Repeated MRI scans were then performed using different sequences, and the degree of the inflammation was evaluated both by image analysis and in the traditional way by inflammatory cell count in lung lavage fluid. The results showed excellent agreement between the severity of the inflammation as determined by image analysis and the degree of the inflammation derived from the inflammatory cell count [1, 2].

The already established and available proton-based methods will be further refined and enhanced in the future. To this end, the scientists are developing imaging sequences enabling quantification of local ventilation, blood flow, and gas exchange after administration of gaseous contrast agents. The CRC Hannover offers an unrivaled infrastructure and setting for this development work: ideal methodological conditions for performing such experiments and thus for developing methods that will enable visualization of inflammatory responses by magnetic resonance imaging, in conjunction with combined expert knowledge potentiated by the close collaboration of Fraunhofer ITEM scientists and radiologists of the Hannover Medical School.

1. Vogel-Claussen J, Renne J, Hinrichs J, Schönfeld C, Gutberlet M, Schaumann F, Winkler C, Faulenbach C, Krug N, Wacker FK, Hohlfeld JM. Quantification of pulmonary inflammation after segmental allergen challenge using turbo-inversion recovery-magnitude magnetic resonance imaging. Am J Respir Crit Care Med. 15. März 2014; 189 (6): 650-7
2. Renne J, Hinrichs J, Schönfeld C, Gutberlet M, Winkler C, Faulenbach C, Jakob P, Schaumann F, Krug N, Wacker F, Hohlfeld JM, Vogel-Claussen J. Noninvasive quantification of airway inflammation following segmental allergen challenge with functional MR imaging: a proof of concept study. Radiology. Jan 2015;274 (1): 267-75

The newly developed MRI methods will enable future study designs including not only efficacy evaluation drug candidates by means of a non-invasive method, but also monitoring of the course of action over time. The methods that have been used so far, namely bronchoscopy and induced sputum, cannot be applied repeatedly, so that generation of this valuable additional information has been impossible to date. Furthermore, the new methods will enable space-resolved insights into the course of the inflammatory process. The methods available so far can only capture the overall inflammation severity without spatial resolution.