The Impact of Particulate Matter-Induced Inflammation in the Mouse Lung

Increased concentrations of airborne particulate matter (PM) have been associated with adverse cardiopulmonary health effects. When controlled studies are performed, inflammation has been observed to be one of the largest biological responses to PM. Inflammation can be either protective or actually add to an initial injury, so it is important to know the impact of PM-induced inflammation. I hypothesized that neutrophilic inflammation in an otherwise healthy animal exhibits protective effects in the lung after PM administration. To test this hypothesis, I first identified biological responses that occurred in the mouse lung before peak neutrophil recruitment. I then inhibited neutrophil recruitment to the lung and looked to see how the early responses might change using PM collected from a wildfire episode. Preliminary studies to look at groups that may be susceptible to PM-induced inflammation were also performed using mice that were previously inoculated with a mouse-adapted influenza virus. Pulmonary macrophage-specific cytotoxicity and secretion of Clara Cell Secretory Protein from airway epithelial cells were observed immediately after wildfire PM instillation. Furthermore, free isoprostanes, as a measure of oxidative stress, and increased tumor necrosis factor-alpha (TNF-alpha) concentrations, as a measure of pro-inflammatory responses, were seen in the lung lavage of mice instilled with wildfire PM as compared to control groups of mice. All of these responses resolved with the neutrophil influx. However, at the peak of neutrophil recruitment, there were measures of increased cytotoxicity, as shown with increased lactate dehydrogenase (LDH) in the lavage fluid. When neutrophils were inhibited, there were increased TNF-alpha concentrations during the time period when normally both peak PM-induced neutrophilia occurs and TNF-alpha concentrations return to control levels. This prolonged pro-inflammatory response from the lung suggested that neutrophils were important for resolving a PM-induced insult. Contrary to this, there were decreased LDH concentrations with neutrophil inhibition, which suggested a protective effect from preventing neutrophil recruitment. However, since the LDH assay is not cell specific, further investigation was performed to determine which cell population was undergoing increased cell death. With this, decreased cell proliferation in the airway epithelium was also observed with inhibition of PM-induced neutrophilia. Because cell proliferation of the airway epithelium does not occur simultaneously with its cell death, the observed increase in LDH may be more indicative of neutrophil cell death and resolution of neutrophilic inflammation. When comparing PM-induced inflammatory responses in healthy mice versus mice that were intranasally instilled with virus, there were trends toward increased inflammation in viral-infected mice, but there was no evidence of increased cytotoxicity. In conclusion, in an otherwise healthy, adult mouse the acute neutrophilic inflammatory response seems to have a positive impact. Furthermore, in mice with more intense PM-induced inflammation, increased cytotoxicity was not observed. This work suggests that susceptible populations to airborne particulate matter may be individuals who are immunodeficient.