Proton MRI of lung parenchyma reflects allergen‐induced airway remodeling and endotoxin‐aroused hyporesponsiveness: A step toward ventilation studies in spontaneously breathing rats

Abstract

Proton signals from lung parenchyma were detected with the use of a gradient-echo sequence to noninvasively obtain information on pulmonary function in models of airway diseases in rats. Initial measurements carried out in artificially ventilated control rats revealed a highly significant negative correlation between the parenchymal signal and the partial pressure of oxygen (pO 2 ) in the blood, for different amounts of oxygen administered. The magnitude of the signal intensity variations caused by changes in the oxygen concentration was larger than expected solely from the paramagnetic properties of molecular oxygen. Key words: airway remodeling; asthma; chronic obstructive pulmonary disease (COPD); lung; lung ventilation; magnetic resonance imaging (MRI); oxygen-enhanced MRI; rat; ventilation Several animal models have been developed in an attempt to mimic and study specific aspects of human respiratory diseases (1,2). For instance, actively sensitized Brown Norway (BN) rats exposed to allergens develop airway hyperresponsiveness and an eosinophilic inflammation together with an increase in activated T cells (CD25ϩ) in the airways (3,4), and thus manifest some key features of asthmatic inflammation. Also, an inflammation that shows some characteristics of chronic obstructive pulmonary disease (COPD) can be elicited in rodents by the administration of endotoxin (lipopolysaccharide (LPS)), a bacterial macromolecular cell surface antigen (5,6).In pharmacological studies of pulmonary inflammation at the preclinical level, histology and analysis of bronchoalveolar lavage fluid are routinely used to assess the inflammatory status of the lung and the results of drug intervention. Although they provide comprehensive information at the cellular level, these methods have the drawback of being terminal. It was recently shown that proton MRI can be used to noninvasively characterize the inflammatory status of the rat lungs following allergen (7) or endotoxin (8) challenge. The significant correlation between the MRI signals and the perivascular edema determined by histology provides a basis for the noninvasive assessment of a key component of inflammation in the allergen model (9). With this approach, one can assess the rapid effects of drugs in vivo by monitoring the rate at which edematous signals resolve. In addition, the prospect of using MRI to noninvasively detect a sustained mucus hypersecretory phenotype induced by endotoxin brings an important new perspective to models of COPD in animals.Inflammation in airways leads to pathophysiologic changes in the structure of the lung tissue, including thickening of the smooth muscle in the airway wall (10), which can influence airway responsiveness (11), as well as ventilation. The progressive structural change known as airway remodeling, which is driven by chronic local inflammation, is a fundamental component in the development of irreversible airway hyperresponsiveness (for a recent review, see Ref. 12).The aim of the present work was to monitor noninvasively by MRI the ...

A View on Imaging in Drug Research and Development for Respiratory Diseases

“…Regional lung ventilation and volume were measured with electrical impedance tomography in piglets (Richard et al, 2009). Proton MRI detected, in spontaneously breathing rats, the effects of broncho-modulating agents (Beckmann et al, 2006) or inflammation-induced airway remodeling and hyporesponsiveness in OVA-or LPS-challenged animals, respectively (Beckmann et al, 2004). The approach consists of detecting modulations of lung parenchymal proton signals induced by changes in oxygenation levels, increases in parenchymal signal being linked with a reduced oxygen level, and vice versa (Edelman et al, 1996).…”

Bleomycin‐induced lung injury assessed noninvasively and in spontaneously breathing rats by proton MRI

“…The readouts were as follows: 1) fluid signals reflecting the acute edematous response to BLM; and 2) parenchymal signal intensity changes due to structural alterations of the lung tissue (18,19). Measurements were performed in spontaneously breathing rats, and neither cardiac nor respiratory gating was used.…”

Morphological and functional imaging in COPD with CT and MRI: present and future

“…The combination of T2-weighted and ce T1-weighted sequences may be an attractive alternative for imaging of airway inflammation without radiation (Figs. 1, 4) [40].…”