Pulmonary edema measured by MRI correlates with late-phase response to allergen challenge.

PURPOSE: Asthma is associated with reversible airway obstruction, leucocyte infiltration, airways hyperresponsiveness (AHR), and airways remodeling. Fluid accumulation causes pulmonary edema contributing to airways obstruction. We examined the temporal relationship between the late asthmatic response (LAR) following allergen challenge of sensitized guinea-pigs and pulmonary edema measured by magnetic resonance imaging (MRI). MATERIALS AND METHODS: Ovalbumin (OVA) sensitized guinea-pigs received either a single OVA inhalation (acute) or nine OVA inhalations at 48 h intervals (chronic). Airways obstruction was measured as specific airways conductance (sG(aw)) by whole body plethysmography. AHR to inhaled histamine and bronchoalveolar lavage for leucocyte counts were measured 24 h after a single or the final chronic ovalbumin challenges. MRI was performed at intervals after OVA challenge and high-intensity edemic signals were quantified. RESULTS: Ovalbumin caused early bronchoconstriction, followed at 7 h by an LAR and at 24 h AHR and leucocyte influx. The bright-intensity MRI edema signal, peaking at 7 h, was significantly (P < .05) greater after chronic (9.0 ± 0.7 × 10(3) mm(3)) than acute OVA (7.6 ± 0.2 × 10(3) mm(3)). Dexamethasone treatment before acute OVA abolished the AHR and LAR and significantly reduced eosinophils and the bright-intensity MRI edema from 9.1 ± 1.0 to 6.4 ± 0.3 × 10(3) mm(3). CONCLUSION: We show a temporal relationship between edema and the LAR and their parallel reduction, along with eosinophils and AHR, by dexamethasone. This suggests a close causative association between pulmonary edema and impaired airways function.

Longitudinal characterization of a model of chronic allergic lung inflammation in mice using imaging, functional and immunological methods.

The present study investigated the role that imaging could have for assessing lung inflammation in a mouse model of HDM (house dust mite)-provoked allergic inflammation. Inflammation is usually assessed using terminal procedures such as BAL (bronchoalveolar lavage) and histopathology; however, MRI (magnetic resonance imaging) and CT (computed tomography) methods have the potential to allow longitudinal, repeated study of individual animals. Female BALB/c mice were administered daily either saline, or a solution of mixed HDM proteins sufficient to deliver a dose of 12 or 25 µg total HDM protein±budesonide (1 mg/kg of body weight, during weeks 5-7) for 7 weeks. AHR (airway hyper-responsiveness) and IgE measurements were taken on weeks 3, 5 and 7. Following imaging sessions at weeks 3, 5 and 7 lungs were prepared for histology. BAL samples were taken at week 7 and lungs prepared for histology. MRI showed a gradual weekly increase in LTI (lung tissue intensity) in animals treated with HDM compared with control. The 25 µg HDM group showed a continual significant increase in LTI between weeks 3 and 7, the 12 µg HDM-treated group showed a similar rate of increase, and plateaued by week 5. A corresponding increase in AHR, cell counts and IgE were observed. CT showed significant increases in lung tissue density from week 1 of HDM exposure and this was maintained throughout the 7 weeks. Budesonide treatment reversed the increase in tissue density. MRI and CT therefore provide non-invasive sensitive methods for longitudinally assessing lung inflammation. Lung tissue changes could be compared directly with the classical functional and inflammatory readouts, allowing more accurate assessments to be made within each animal and providing a clinically translatable approach.

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems.

BACKGROUND: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking. OBJECTIVE: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. METHODS: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days. R1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured. RESULTS: CoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R1-based MR biomarkers were found to be quite sensitive even to such small errors in R1, notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s-1 mM-1 at 3 T and 0.94 s-1 mM-1 at 11.7T. INTERPRETATION: While several factors affect the reproducibility of R1-based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R1-reproducibility.

Effect of the TRPV1 antagonist SB-705498 on the nasal parasympathetic reflex response in the ovalbumin sensitized guinea pig.

BACKGROUND AND PURPOSE: Nasal sensory nerves play an important role in symptoms associated with rhinitis triggered by environmental stimuli. Here, we propose that TRPV1 is pivotal in nasal sensory nerve activation and assess the potential of SB-705498 as an intranasal therapy for rhinitis. EXPERIMENTAL APPROACH: The inhibitory effect of SB-705498 on capsaicin-induced currents in guinea pig trigeminal ganglion cells innervating nasal mucosa was investigated using patch clamp electrophysiology. A guinea pig model of rhinitis was developed using intranasal challenge of capsaicin and hypertonic saline to elicit nasal secretory parasympathetic reflex responses, quantified using MRI. The inhibitory effect of SB-705498, duration of action and potency comparing oral versus intranasal route of administration were examined. KEY RESULTS: SB-705498 concentration-dependently inhibited capsaicin-induced currents in isolated trigeminal ganglion cells (pIC50 7.2). In vivo, capsaicin ipsilateral nasal challenge (0.03-1 mM) elicited concentration-dependent increases in contralateral intranasal fluid secretion. Ten per cent hypertonic saline initiated a similar response. Atropine inhibited responses to either challenge. SB-705498 inhibited capsaicin-induced responses by ∼50% at 10 mg·kg⁻¹ (oral), non-micronized 10 mg·mL⁻¹ or 1 mg·mL⁻¹ micronized SB-705498 (intranasal) suspension. Ten milligram per millilitre intranasal SB-705498, dosed 24 h prior to capsaicin challenge produced a 52% reduction in secretory response. SB-705498 (10 mg·mL⁻¹, intranasal) inhibited 10% hypertonic saline responses by 70%. CONCLUSIONS AND IMPLICATIONS: The paper reports the development of a guinea pig model of rhinitis. SB-705498 inhibits capsaicin-induced trigeminal currents and capsaicin-induced contralateral nasal secretions via oral and intranasal routes; efficacy was optimized using particle-reduced SB-705498. We propose that TRPV1 is pivotal in initiating symptoms of rhinitis.