Inhalation exposure systems for the development of rodent models of sulfur mustard-induced pulmonary injury.

Sulfur mustard (SM) is a chemical threat agent for which its effects have no current treatment. Due to the ease of synthesis and dispersal of this material, the need to develop therapeutics is evident. The present manuscript details the techniques used to develop SM laboratory exposure systems for the development of animal models of pulmonary injury. These models are critical for evaluating SM injury and developing therapeutics against that injury. Iterative trials were conducted to optimize a lung injury model. The resulting pathology was used as a guide, with a goal of effecting homogeneous and diffuse lung injury comparable to that of human injury. Inhalation exposures were conducted by either nose-only inhalation or intubated inhalation. The exposures were conducted to either directly vaporized SM or SM that was nebulized from an ethanol solution. Inhalation of SM by nose-only inhalation resulted in severe nasal epithelial degeneration and minimal lung injury. The reactivity of SM did not permit it to transit past the upper airways to promote lower airway injury. Intratracheal inhalation of SM vapors at a concentration of 5400 mg x min/m(3) resulted in homogeneous lung injury with no nasal degeneration.

Development of a head-out plethysmograph system for non-human primates in an Animal Biosafety Level 3 facility.

INTRODUCTION: The term 'select agent' (SA) refers to a list of microorganisms and toxins and are defined as those that have the potential to pose a severe threat to public health and safety (42 C.F.R. Part 73). In order to carry out a research with SAs, an Animal Biosafety Level 3 (ABSL3) containment facility is required. Our newly completed ABSL3 facility is developing protocols for implementing safety and efficacy studies of therapeutics for SAs. METHODS: The primary purpose of this study was to develop methods for exposing non-human primates (NHP) to aerosolized SAs in the ABSL3 and systematically measure specific ventilatory endpoints (frequency, tidal volume, minute volume, and accumulated volume) using a head-out plethysmograph to more precisely control dosimetry. This report details the equipment and protocols used to conduct such studies within a containment facility. RESULTS: After validating the performance of the plethysmography system, we successfully exposed NHPs to an agent using the integrated plethysmography system. The system enabled an acquisition and analysis of ventilatory characteristics, facilitating accurate estimations of the inhaled dose. DISCUSSION: This system will have clear uses in the development of novel therapeutics and vaccines for the treatment of SAs in NHPs.

Modulators of cigarette smoke-induced pulmonary emphysema in A/J mice.

Mice develop pulmonary emphysema after chronic exposure to cigarette smoke (CS). In this study, the influence of gender, exposure duration, and concentration of CS on emphysema, pulmonary function, inflammation, markers of toxicity, and matrix metalloproteinase (MMP) activity was examined in A/J mice. Mice were exposed to CS at either 100 or 250 mg total particulate material/m(3) (CS-100 or CS-250, respectively) for 10, 16, or 22 weeks. Evidence of emphysema was first seen in female mice after 10 weeks of exposure to CS-250, while male mice did not develop emphysema until 16 weeks. Female mice exposed to CS-100 did not have emphysema until 16 weeks, suggesting that disease development depends on the concentration and duration of exposure. Airflow obstruction and increased pulmonary compliance were observed in mice exposed to CS-250 for 22 weeks. Decreased elasticity was likely the major contributor to airflow obstruction because substantial remodeling of the conducting airways, beyond mild mucous cell hyperplasia, was lacking. Exposure to CS increased the number of macrophages, neutrophils, lymphocytes (B cells and activated CD4- and CD8-positive T cells), and activity of MMP-2 and -9 in the bronchoalveolar lavage fluid (BALF). Treatment with antioxidants N-acetylcysteine or epigallocatechin gallate (EGCG) did not decrease emphysema severity, but EGCG slightly decreased BALF inflammatory cell numbers and lactate dehydrogenase activity. Inflammation and emphysema persisted after a 17-week recovery period following exposure to CS-250 for 22 weeks. The similarities of this model to the human disease make it promising for studying disease pathogenesis and assessing new therapeutic interventions.