Detection of lung dysfunction using ventilation and perfusion SPECT in a mouse model of chronic cigarette smoke exposure.

UNLABELLED: Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality worldwide. Exposure to cigarette smoke (CS) is a major risk factor for developing this chronic airflow impairment, but the early progression of disease is not well defined or understood. Ventilation/perfusion (V/Q) SPECT provides a noninvasive assessment of lung function to further our current understanding of how CS affects the lung. METHODS: BALB/c mice were imaged with V/Q SPECT and CT after 8 and 24 wk of whole-body exposure to mainstream CS. Bronchoalveolar lavage was collected and cell differentials produced to determine inflammatory patterns. Histologic lung sections were collected, and a semiautomated quantitative analysis of airspace enlargement was applied to whole histology slices. RESULTS: Exposure to CS induced an inflammatory response that included increases in the numbers of both mononuclear cells and neutrophils. Airspace enlargement was also significantly increased at 8 wk of CS exposure and was still more pronounced at 24 wk. Ventilation and perfusion correlation at the voxel level depicted a significant decrease in matching at 8 wk of CS exposure that was also apparent after 24 wk. The standard deviation (SD) of the log(V/Q) curve, a basic measure of heterogeneity, was increased from 0.44 ± 0.02 in age-matched controls to 0.62 ± 0.05 with CS exposure at 24 wk, indicating an increase in V/Q mismatching between 8 and 24 wk of CS exposure. CT, however, was not capable of discriminating control from CS-exposed animals at either time point, even with greater resolution and respiratory gating. CONCLUSION: This study demonstrated that, before CT detection of structural changes, V/Q imaging detected changes in gas-exchange potential. This functional impairment corresponded to increased lung inflammation and increased airspace enlargement. In vivo V/Q imaging can detect early changes to the lung caused by CS exposure and thus provides a noninvasive method of longitudinally studying lung dysfunction in preclinical models. In the future, these measures could be applied clinically to study and diagnose the early stages of chronic obstructive pulmonary disease.

Imaging lung function in mice using SPECT/CT and per-voxel analysis.

Chronic lung disease is a major worldwide health concern but better tools are required to understand the underlying pathologies. Ventilation/perfusion (V/Q) single photon emission computed tomography (SPECT) with per-voxel analysis allows for non-invasive measurement of regional lung function. A clinically adapted V/Q methodology was used in healthy mice to investigate V/Q relationships. Twelve week-old mice were imaged to describe normal lung function while 36 week-old mice were imaged to determine how age affects V/Q. Mice were ventilated with Technegas™ and injected with (99m)Tc-macroaggregated albumin to trace ventilation and perfusion, respectively. For both processes, SPECT and CT images were acquired, co-registered, and quantitatively analyzed. On a per-voxel basis, ventilation and perfusion were moderately correlated (R = 0.58±0.03) in 12 week old animals and a mean log(V/Q) ratio of -0.07±0.01 and standard deviation of 0.36±0.02 were found, defining the extent of V/Q matching. In contrast, 36 week old animals had significantly increased levels of V/Q mismatching throughout the periphery of the lung. Measures of V/Q were consistent across healthy animals and differences were observed with age demonstrating the capability of this technique in quantifying lung function. Per-voxel analysis and the ability to non-invasively assess lung function will aid in the investigation of chronic lung disease models and drug efficacy studies.

Fetal and neonatal exposure to nicotine disrupts postnatal lung development in rats: role of VEGF and its receptors.

Many women are unable to quit smoking during pregnancy and therefore are prescribed drugs, including nicotine (nicotine replacement therapy [NRT]), to aid with smoking cessation. However, the consequences to the offspring of pregnant NRT users have not been well studied. The goals of this study were to determine the consequences of fetal and neonatal exposure to nicotine on lung development and function. Female rats were exposed to nicotine for 2 weeks prior to mating until weaning. Lungs were collected from saline and nicotine-treated rats from birth to adulthood to assess postnatal lung structure and function. Although nicotine exposure altered alveolarization at weaning, an effect that resolved by adulthood, it did not affect lung function at any of the ages investigated. However, nicotine exposure significantly decreased lung vascularization. The current study suggests that perinatal exposure to nicotine alters lung development, an effect which may be mediated via decreased vascular endothelial growth factor (VEGF) signaling.

Lung perfusion imaging with monosized biodegradable microspheres.

After intravenous injection, particles larger than red blood cells will be trapped in the first capillary bed that they encounter. This is the principle of lung perfusion imaging in nuclear medicine, where macroaggregated albumin (MAA) is radiolabeled with (99m)Tc, infused into a patient's arm vein, and then imaged with gamma scintigraphy. Our aim was to evaluate if monosized microspheres could replace (99m)Tc-MAA. Biodegradable poly(L-lactide) microspheres containing chelating bis(picolylamine) end groups were prepared by a flow focusing method on a microfluidic glass chip and were of highly homogeneous size (9.0 +/- 0.4 microm). The microspheres were radiolabeled with [(99m)Tc(H(2)O)(3)(CO)(3)](+) and then evaluated in mice for lung perfusion imaging. Fifteen minutes after injection, 79.6 +/- 3.8% of the injected activity was trapped in the lungs of mice. Monosized biodegradable radioactive microspheres are, thus, appropriate lung perfusion imaging agents. Other sizes of these highly uniform microspheres have the potential to improve diagnostic and therapeutic approaches in diverse areas of medicine.

Systematic overview of drug interactions with antidepressant medications.

OBJECTIVE: Antidepressants are commonly used drugs with potential for numerous drug interactions. This study aims to systematically review the literature on drug interactions with antidepressants. METHODS: We searched MEDLINE (1966 to November 2003) and EMBASE (1980 to 2003), using the heading drug interactions combined with individual antidepressant names. We restricted searches to English-language articles and human studies. We screened drug interaction texts and review articles for relevant studies. We included articles reporting original human data on drug interactions with antidepressants commonly used in North America. Articles were independently evaluated by 2 reviewers on clinical effect, clinical significance, and quality of evidence. Discrepancies were resolved by consensus. RESULTS: There were 904 eligible interactions, involving 9509 patients, for a total of 598 summary interactions. Of these, 439 (73%) demonstrated an interaction, 148 (25%) had no effect, and 11 (2%) had conflicting evidence. For 510 interactions (85%), the quality of evidence was poor. It was fair for 67 (11%) interactions and good for 10 (2%) interactions. There were no interactions with excellent quality of evidence. There were 145 (24%) interactions of major clinical significance. These were predominantly hypertensive emergencies and serotonin syndrome. Most interacting drugs had central nervous system (CNS) activity. As expected, monoamine oxidase inhibitors (MAOIs) appear to be the most problematic family in terms of potential for serious drug interactions. CONCLUSIONS: Drug interactions with antidepressants are an important cause for concern, but this concern is based primarily on poor evidence. We recommend caution when combining antidepressants with other CNS drugs, particularly when coadministering MAOIs with other substances.