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.

Human parainfluenza type 3 virus impairs the efficacy of glucocorticoids to limit allergy-induced pulmonary inflammation in guinea-pigs.

Viral exacerbations of allergen-induced pulmonary inflammation in pre-clinical models reportedly reduce the efficacy of glucocorticoids to limit pulmonary inflammation and airways hyper-responsiveness to inhaled spasmogens. However, exacerbations of airway obstruction induced by allergen challenge have not yet been studied. hPIV-3 (human parainfluenza type 3 virus) inoculation of guinea-pigs increased inflammatory cell counts in BAL (bronchoalveolar lavage) fluid and caused hyper-responsiveness to inhaled histamine. Both responses were abolished by treatment with either dexamethasone (20 mg/kg of body weight, subcutaneous, once a day) or fluticasone propionate (a 0.5 mg/ml solution aerosolized and inhaled over 15 min, twice a day). In ovalbumin-sensitized guinea-pigs, allergen (ovalbumin) challenge caused two phases of airway obstruction [measured as changes in sGaw (specific airways conductance) using whole body plethysmography]: an immediate phase lasting between 4 and 6 h and a late phase at about 7 h. The late phase, airway hyper-responsiveness to histamine and inflammatory cell counts in BAL were all significantly reduced by either glucocorticoid. Inoculation of guinea-pigs sensitized to ovalbumin with hPIV-3 transformed the allergen-induced airway obstruction from two transient phases into a single sustained response lasting up to 12 h. This exacerbated airway obstruction and airway hyper-responsiveness to histamine were unaffected by treatment with either glucocorticoid whereas inflammatory cell counts in BAL were only partially inhibited. Virus- or allergen-induced pulmonary inflammation, individually, are glucocorticoid-sensitive, but in combination generate a phenotype where glucocorticoid efficacy is impaired. This suggests that during respiratory virus infection, glucocorticoids might be less effective in limiting pulmonary inflammation associated with asthma.

A comparison of antiasthma drugs between acute and chronic ovalbumin-challenged guinea-pig models of asthma.

Pre-clinical evaluation of asthma therapies requires animal models of chronic airways inflammation, airway hyperresponsiveness (AHR) and lung remodelling that accurately predict drug effectiveness in human asthma. However, most animal models focus on acute allergen challenges where chronic inflammation and airway remodelling are absent. Chronic allergen challenge models have been developed in mice but few studies use guinea-pigs which may be more relevant to humans. We tested the hypothesis that a chronic rather than acute pulmonary inflammation model would best predict clinical outcome for asthma treatments. Guinea-pigs sensitized with ovalbumin (OVA) received single (acute) or nine OVA inhalation challenges at 48 h intervals (chronic). Airways function was recorded as specific airways conductance (sG(aw)) in conscious animals for 12 h after OVA challenge. AHR to inhaled histamine, inflammatory cell influx and lung histology were determined 24 h after the single or 9th OVA exposure. The inhaled corticosteroid, fluticasone propionate (FP), the phosphodiesterase 4 inhibitor, roflumilast, and the inducible nitric oxide synthase (iNOS) inhibitor, GW274150, orally, were administered 24 and 0.5 h before and 6 h after the single or final chronic OVA exposure. Both models displayed early (EAR) and late (LAR) asthmatic responses to OVA challenge, as falls in sG(aw), AHR, as increased histamine-induced bronchoconstriction, and inflammatory cell influx. Tissue remodelling, seen as increased collagen and goblet cell hyperplasia, occurred after multiple OVA challenge. Treatment with FP and roflumilast inhibited the LAR, cell influx and AHR in both models, and the remodelling in the chronic model. GW274150 also inhibited the LAR, AHR and eosinophil influx in the acute model, but not, together with the remodelling, in the chronic model. In the clinical setting, inhaled corticosteroids and phosphodiesterase 4 inhibitors are relatively effective against most features of asthma whereas the iNOS inhibitor GW274150 was ineffective. Thus, while there remain certain differences between our data and clinical effectiveness of these antiasthma drugs, a chronic pulmonary inflammation guinea-pig model does appear to be a better pre-clinical predictor of potential asthma therapeutics than an acute model.

Paracetamol reduces influenza-induced immunopathology in a mouse model of infection without compromising virus clearance or the generation of protective immunity.

BACKGROUND: Seasonal influenza A infection affects a significant cohort of the global population annually, resulting in considerable morbidity and mortality. Therapeutic strategies are of limited efficacy, and during a pandemic outbreak would only be available to a minority of the global population. Over-the-counter medicines are routinely taken by individuals suffering from influenza, but few studies have been conducted to determine their effectiveness in reducing pulmonary immunopathology or the influence they exert upon the generation of protective immunity. METHODS: A mouse model of influenza infection was utilised to assess the efficacy of paracetamol (acetaminophen) in reducing influenza-induced pathology and to examine whether paracetamol affects generation of protective immunity. RESULTS: Administration (intraperitoneal) of paracetamol significantly decreased the infiltration of inflammatory cells into the airway spaces, reduced pulmonary immunopathology associated with acute infection and improved the overall lung function of mice, without adversely affecting the induction of virus-specific adaptive responses. Mice treated with paracetamol exhibited an ability to resist a second infection with heterologous virus comparable with that of untreated mice. CONCLUSIONS: Our results demonstrate that paracetamol dramatically reduces the morbidity associated with influenza but does not compromise the development of adaptive immune responses. Overall, these data support the utility of paracetamol for reducing the clinical symptoms associated with influenza virus infection.

To breed or not to breed? Empirical evaluation of drug effects in adolescent rats.

The recent upsurge of research on adolescent rats raises the issue of the extent to which different methods of rodent procurement might affect results. Here, we examined the effects of acute and repeated dosing with two antipsychotics, haloperidol and clozapine, and Delta(9)-tetrahydrocannabinol [Experiments 1 and 2, respectively] in adolescent rats of both sexes that differed in shipping status (i.e., shipped from a commercial breeder at weaning or bred in-house). In each experiment, test drugs produced effects that were characteristic for their respective classes in previous studies with adult rodents. Both haloperidol and clozapine produced catalepsy and haloperidol decreased locomotion in shipped and bred rats of both sexes, with sensitization to haloperidol-induced catalepsy developing with repeated dosing. The most prominent between-status difference in this experiment was greater sensitivity of the shipped rats to haloperidol-induced changes in locomotor activity over a wider dose range, an effect that was especially evident in females. In Experiment 2, vehicle levels of motor activity were decreased in bred rats (which did not occur in Experiment 1), resulting in flattening of the Delta(9)-tetrahydrocannabinol dose-effect curve for this measure in bred rats of each sex. Acutely, Delta(9)-tetrahydrocannabinol produced antinociception, hypothermia and catalepsy in both groups of rats, with tolerance developing after repeated dosing. Status-related differences were sex-dependent. Whereas bred female rats were more sensitive to Delta(9)-tetrahydrocannabinol's antinociceptive effects, shipped male rats were more sensitive to its antinociceptive effects as well as to its hypothermic and cataleptic effects. Together, the results of these descriptive experiments suggest that between-status differences tend to be quantitative rather than qualitative. Further, these results suggest that careful attention to issues related to rodent procurement during adolescence is warranted and may help to account for divergent findings in different labs.

Age-dependent differences in sensitivity and sensitization to cannabinoids and 'club drugs' in male adolescent and adult rats.

Lifelong substance abuse is often initiated during adolescence; yet, most pre-clinical research in this area has been conducted in adult animals. Substantial evidence exists that the brain development that continues throughout adolescence may result in pharmacological responses that differ in a crucial manner from those of adults. The goal of this study was to evaluate age differences in motor activity following acute and repeated administration of drugs that are commonly abused by adolescents, including cocaine, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), and the club drugs, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Adolescent and adult male rats were injected once daily with saline or with a dose of one of the test drugs for two 5-day dosing periods, separated by a 2-day drug holiday during which they remained in their home cages. Following each injection, rats were placed in a locomotor chamber for a 20-minute session. The potencies of cocaine, ketamine and MDMA for producing motor stimulation were less in male adolescents than in male adults. Furthermore, sensitization to the club drug, ketamine, developed after repeated dosing in adults, but not adolescents. In contrast, adolescents were initially more sensitive to the stimulatory effects of low doses of Delta(9)-THC than were adults, although rapid tolerance occurred. These results suggest that adolescents are less sensitive to the acute and repeated stimulant effects of some, but not all, of the drugs that are preferentially abused by this age group. This differential sensitivity may contribute to the different patterns of use that have been noted in adolescent versus adult drug abusers.

Molecular imaging in the development of a novel treatment paradigm for glioblastoma (GBM): an integrated multidisciplinary commentary.

Current therapeutic strategies against glioblastoma (GBM) have failed to prevent disease progression and recurrence effectively. The part played by molecular imaging (MI) in the development of novel therapies has gained increasing traction in recent years. For the first time, using expertise from an integrated multidisciplinary group of authors, herein we present a comprehensive evaluation of state-of-the-art GBM imaging and explore how advances facilitate the emergence of new treatment options. We propose a novel next-generation treatment paradigm based on the targeting of multiple hallmarks of cancer evolution that will heavily rely on MI.

Locomotor activity changes in female adolescent and adult rats during repeated treatment with a cannabinoid or club drug.

Adolescents and young adults of both sexes are the primary consumers of "club" drugs; yet, most of the mechanistic preclinical research in this area has been performed in adult male rodents. The purpose of this study was to evaluate the acute and repeated effects of drugs that are commonly abused by adolescents in female adolescent and adult rats in a rodent model of behavioral sensitization. During two five-day periods separated by a two-day break, rats were injected daily with saline or with one of the following drugs: cocaine (7 or 15 mg/kg), ketamine (3 or 10 mg/kg), 3,4-methylenedioxymethamphetamine (MDMA) (3, 10, or 30 mg/kg), or Δ(9)-tetrahydrocannabinol (THC) (0.03, 0.1, 0.3 or 1 mg/kg) and their locomotor activity was measured. Cocaine increased activity across days in both age groups. Whereas ketamine produced progressive increases in activity with repeated administration in rats of both ages, MDMA increased, and then decreased, activity in the chronic dosing regimen in female adolescents only. Tolerance to the initial stimulatory effects of low doses of THC was observed at both ages. The results with THC are similar to those obtained for male rats tested under identical conditions in a previous study; however, in contrast with the present results in females, male adolescent rats in the previous study failed to develop behavioral sensitization to ketamine. Together, these results suggest that age and sex strongly influence the progressive adaptive changes that occur with repeated administration of some, but not all, of these commonly abused substances.

Evaluation of age and sex differences in locomotion and catalepsy during repeated administration of haloperidol and clozapine in adolescent and adult rats.

Adolescence is associated with characteristic behavioral patterns as well as with substantial neuronal pruning and re-organization of the brain. Recent research has determined that the effects of various centrally active drugs differ in adolescents and adults. This study examined the motor effects of two prototypic antipsychotics in adult [>postnatal day 70 (PN70)] and adolescent (PN30-PN39) rats. Rats were injected daily with saline, 0.3 mg/kg haloperidol, or 10 mg/kg clozapine for 10 days and activity and catalepsy were measured. Adolescents of both sexes were less sensitive to the cataleptic effects of haloperidol than were adults. Male adolescents were also less sensitive to the cataleptic effects of clozapine, although this difference was transitory. In contrast, female adults showed decreased sensitivity to clozapine's effects, differing from all other groups. These results suggest that adolescents of both sexes may be less sensitive to the extrapyramidal motor effects of haloperidol. Translational implications of the clozapine results are less clear; however, results suggest that developmental differences in neurochemical systems affected by clozapine that are also related to motor behavior may play a role. These results also emphasize the importance of age and sex as determinants of the pharmacological effects of these antipsychotics.