The primary focus of the laboratory is the elucidation of the molecular and cellular mechanisms of lung injury (inflammation and fibrosis) from a diverse array of agents.  Our laboratory has a pulmonary disease research emphasis with expertise in macrophage biology and immune disregulation.  The goals of the studies are to develop strategies to identify subjects at greatest risk of developing lung injury, develop new methods/pharmacologic tools to prevent or halt to progress of lung inflammation and evaluate the risk of human disease from environmentally and occupationally-derived toxic agents.  Listed below are brief summaries of ongoing projects.

Nanomaterials Toxicity: As reported by the National Academy of Sciences, the development of nanomaterials is outpacing the evaluation of potential risk that these materials may be causing to the environment and human health.  Our laboratory has ongoing projects funded by NIH and NSF to determine what health effects could be caused by nanomaterials, their mechanism(s) of action and what characteristics of nanomaterials are most likely to lead to toxic effects.  We have established that carbon nanotubes and titanium nanowires cause lung inflammation, granulomas and fibrosis.  In vitro studies have shown that macrophage cell lines are poor models for primary macrophages where nanowires induce macrophage apoptosis and necrosis. Both in vivo and in vitro studies indicate that the order of potency is long nanowires > short nanowires >> nanospheres with respect to toxicity and lung injury.  This outcome suggested that something other than surface chemistry is responsible for unique toxicity of nanowires and current research supports the hypothesis that the toxicity is directly proportional to lysosomal disruption.  Current research is examining the mechanisms responsible for membrane recognition, lysosomal disruption, design of safe nanomaterials and pharmacological intervention to limit lung pathologies resulting from exposures to these materials.

Silica and Scavenger Receptors:  We have utilized crystalline silica as a model toxic particulate to study the mechanisms involved in the development of lung fibrosis that may be caused by various agents or unknown in the case of idiopathic lung fibrosis.  Since no effective therapeutic approaches are currently in practice this presents an important challenge.  Ongoing NIH-funded projects are examining: 1) the role of signaling mechanisms in inflammasome activation in macrophages and therapeutic interventions using in vivo models in the development of lung fibrosis as well as autoimmune disease; 2) contribution of other immune cells to disease pathology; and 3) the protective role that the scavenger receptor MARCO plays in preventing lung inflammation. 

Asbestos Research:  Similar to silica, asbestos is known to cause lung fibrosis and appears to enhance autoimmune diseases. There are a number of different forms of asbestos with amphiboles forms considered more toxic than chrysotile, which is a serpentine fiber.  Over the past few years interest has increased in a somewhat different form of amphibole that contaminated vermiculite mined in Libby, MT.  This Libby amphibole has been responsible for a high frequency of occupationally linked cases of asbestos related diseases and environmentally associated cases.  Not only is the composition different, but also the sizes of the fibers are smaller.  These differences as well as the real world diseases that exist in Libby pose significant challenges and needs to identify mechanisms of action of these fibers in disease causation in order to develop therapeutic intervention.  Current studies are examining the roles of fiber size in toxicity and pathological outcomes as well as mechanisms of toxicity.

Methamphetamine:  While it has been well recognized that methamphetamine is a highly addictive drug our studies have shown that smoking methamphetamine causes acute lung injury as well as severe constriction of blood vesicles in the heart.  These outcomes may explain the anecdotal and published observations that children taken from homes, where methamphetamine exposures have occurred, have acute respiratory distress while users develop cardiovascular complications.  Our CDC funded research program has shown that relatively low exposures increase airway hyper-reactivity as well as cardiovascular changes in murine models.  Our current focus is developing information on mechanisms to explain these events with the goal of providing caregivers and first responders new information on dealing with children and others who have been exposed to methamphetamine smoke.

Biomass smoke:  Many studies have now shown that exposure to respirable particulate matter (PM2.5) causes a variety of health effects and that living in an environment with cleaner air increases life expectancy.  There is increasing evidence that maternal exposures to particulate matter may lead to epigenetic changes.  Since exposures to biomass smoke can be very high in indoor environments in homes with wood stoves (in rural settings as well as in developing countries) and during wildfire events our focus is on potential epigenetic changes from biomass smoke exposures that may predispose children towards development of asthma.