Nitrogen mustard is a vesicant that causes damage to the respiratory tract. In these studies, we characterized the acute effects of nitrogen mustard on lung structure, inflammatory mediator expression, and pulmonary function, with the goal of identifying mediators potentially involved in toxicity. Treatment of rats (male Wistar, 200–225 g) with nitrogen mustard (mechlorethamine hydrochloride, i.t., 0.25 mg/kg) resulted in marked histological changes in the respiratory tract, including necrotizing bronchiolitis, thickening of alveolar septa, and inflammation which was evident within 24 h. This was associated with increases in bronchoalveolar lavage protein and cells, confirming injury to alveolar epithelial regions of the lung. Nitrogen mustard administration also resulted in increased expression of inducible nitric oxide synthase and cyclooxygenase-2, pro-inflammatory proteins implicated in lung injury, in alveolar macrophages and alveolar and bronchial epithelial cells. Expression of connective tissue growth factor and matrix metalloproteinase-9, mediators regulating extracellular matrix turnover was also increased, suggesting that pathways leading to chronic lung disease are initiated early in the pathogenic process. Following nitrogen mustard exposure, alterations in lung mechanics and function were also observed. These included decreases in baseline static compliance, end-tidal volume and airway resistance, and a pronounced loss of methacholine responsiveness in resistance, tissue damping and elastance. Taken together, these data demonstrate that nitrogen mustard induces rapid structural and inflammatory changes in the lung which are associated with altered lung functioning. Understanding the nature of the injury induced by nitrogen mustard and related analogs may aid in the development of efficacious therapies for treatment of pulmonary injury resulting from exposure to vesicants.

Purpose. To compare systemic intravenous and local intratracheal delivery of doxorubicin (DOX), antisense oligonucleotides (ASO) and small interfering RNA (siRNA). Methods. "Neutral" and cationic liposomes were used to deliver DOX, ASO, and siRNA. Liposomes were characterized by dynamic light scattering, zeta-potential, and atomic force microscopy. Cellular internalization of DOX, ASO and siRNA was studied by confocal microscopy on human lung carcinoma cells. In vivo experiments were carried out on nude mice with an orthotopic model of human lung cancer. Results. Liposomes provided for an efficient intracellular delivery of DOX, ASO, and siRNA in vitro. Intratracheal delivery of both types of liposomes in vivo led to higher peak concentrations and much longer retention of liposomes, DOX, ASO and siRNA in the lungs when compared with systemic administration. It was found that local intratracheal treatment of lung cancer with liposomal DOX was more efficient when compared with free and liposomal DOX delivered intravenously. Conclusions. The present study outlined the clear advantages of local intratracheal delivery of liposomal drugs for the treatment of lung cancer when compared with systemic administration of the same drug.

The relationship between microparticle (MP) size and lung targeting efficiency, intra-lung distribution and retention time was systematically studied after intravenous administration of rigid fluorescent polystyrene MPs of various sizes (2, 3, 6 and 10μm) to Sprague-Dawley rats. Total fluorescence was assessed and it was found that 2μm and 3μm MPs readily passed through the lung to the liver and spleen while 10μm MPs were completely entrapped in the lung for the one-week duration of the study. Approximately 84% of 6μm MPs that were initially entrapped in the lung were cleared over the next 2 days and 15% were cleared over the remaining 5 days. A Caliper IVIS® 100 small animal imaging system confirmed that 3μm MPs were not retained in the lung but that 6μm and 10μm MPs were widely distributed throughout the lung. Moreover, histologic examination showed MP entrapment in capillaries but not arterioles. These studies suggest that for rigid MPs the optimal size range required to achieve transient but highly efficiently targeting to pulmonary capillaries after IV injection is >6μm but <10μm in rats and that systemic administration of optimally sized MPs may be an efficient alternative to currently used inhalation-based delivery to the lung. KeywordsPassive pulmonary targeting; Rigid non-biodegradable microparticle; In vivo imaging

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal form of interstitial lung disease. We hypothesized that the local pulmonary delivery of prostaglandin E2 (PGE2) by liposomes can be used for the effective treatment of IPF. To test this hypothesis, we used a murine model of bleomycin-induced IPF to evaluate liposomes which carries PGE2 topically to the lungs. Animal survival, body weight, hydroxyproline content in the lungs, lung histology, mRNA and protein expression were studied. After inhalation delivery, liposomes accumulated predominately in the lungs. In contrast, intravenous administration led to the accumulation of liposomes mainly in kidney, liver, and spleen. Liposomal PGE2 prevented the disturbances in the expression of many genes associated with the development of IPF, substantially restricted inflammation and fibrotic injury in the lung tissues, prevented decrease in body weight, limited hydroxyproline accumulation in the lungs and virtually eliminated mortality of animals after intratracheal instillation of bleomycin. In summary, our data provide evidence that pulmonary fibrosis can be effectively treated by the inhalation administration of liposomal form of PGE2 into the lungs. The results of the present investigations make the liposomal form of PGE2 an attractive drug for the effective inhalation treatment of idiopathic pulmonary fibrosis.

Twenty-four healthy mixed-breed dogs were divided into 4 groups. Group 1 received a placebo PO q12h, group 2 received an average of 16.5 (15.1-17.8) mg/kg buffered aspirin PO q12h, group 3 received an average of 2.2 (2.0-2.4) mg/kg carprofen PO q12h, and group 4 received an average of 12.8 (11.7-13.8) mg/kg etodolac PO q24h (with a placebo in the PM). All treatments continued for 28 consecutive days. Gastroduodenal endoscopy was performed on days Ϫ9, 0, 5, 14, and 28. Multiple gastric biopsies were obtained endoscopically on day Ϫ9 to determine each dog's Helicobacter infection status. Four regions in the stomach and 1 region in the proximal duodenum were evaluated endoscopically, and each was assigned a score from 1 to 11. Scores for each region then were summed to give a total score for each endoscopic evaluation. Erosions and submucosal hemorrhages were seen in all dogs receiving aspirin. Only minor gastric lesions were observed in the carprofen, etodolac, and control groups. No adverse clinical signs were noted in any dog given any treatment. Median total score on days 0, 5, 14, and 28, respectively, were as follows: N onsteroidal anti-inflammatory drugs (NSAIDs) frequently are used for the treatment of musculoskeletal disease in veterinary medicine and are the most common medications used by humans worldwide.1 They generally are recognized for their analgesic, antipyretic, and anti-inflammatory properties. In humans, NSAID therapy is associated with upper gastrointestinal (GI) symptoms in 25% of patients and with ulcers and erosions in 40% of patients. The prevalence of NSAID-induced GI lesions in veterinary medicine is unknown. Adverse effects of NSAID therapy recognized in dogs include gastrointestinal bleeding, ulceration, hepatopathy, and possible nephrotoxicity.2-5 NSAIDinduced GI lesions primarily are thought to be due to the inhibition of prostaglandin synthesis via inhibition of cyclooxygenase.The purpose of the present study was to investigate the adverse GI effects of 2 NSAIDs that recently have been introduced to veterinary medicine, carprofen and etodolac, and compare them with the effects of aspirin (positive control) and a placebo (negative control). The main purpose of this research was to provide information regarding adverse GI effects of drugs that are commonly used in dogs suffering from osteoarthritis. Received October 12, 1998; Revised February 24, 1999; Accepted March 16, 1999. Copyright ᭧ 1999 Material and Methods Acclimation of AnimalsThe study was approved by and met all criteria of the Animal Care Committee, Virginia Polytechnic Institute and State University. Twenty-four random source dogs (14 males, 10 females) were acclimated for 4 weeks. Dogs were treated with ivermectin (Ivomec 1%, MSDAg Vet, Rahway, NJ; 200 g/kg PO once), fenbendazole (Panacur Suspension, Hoeschst, Kansas City, MO; 50 mg/kg PO q24h for 3 days), sulfadimethoxine (Albon, Roche, Nutley, NJ; 50 mg/kg PO once, then 25 mg/kg PO q24h for 14 days), and metronidazole (Flagyl, Searle, Chicago, IL; 50 mg/kg PO q24h ...