Exposure to ozone (O3), a common air pollutant, causes cough, dyspnea, reductions in lung function, increased susceptibility to lung infections, hospitalizations, increased asthma attacks, and even excess deaths. Children, the elderly, the obese, and those with pre-existing respiratory disease are particularly susceptible. O3 exposure causes damage to the epithelial lining, which induces the production of cytokines, the infiltration of macrophages and neutrophils, as well as changes in lung function. While there has been substantial interest in the factors that modify the initial inflammatory response, little attentionhas been paid to the factors involved in the resolution of O3-induced injury. Lack of resolution of injury after initial exposure is likely to worsen damage to the lung upon subsequent responses. Gamma/delta (?) T cells line the subepithelial regions of the lung. ? T cells differ from conventional CD4/8 T cells in that they are primarily involved in maintaining tissue homeostasis and are activated by self-antigens derived from damaged cells. In the aims proposed in this F32 proposal, I will examine the role of ? T cells in the resolution (repair of the epithelial cell liing and clearance of immune cells) of lung injury after subacute O3 exposure (0.3 ppm for 12 to 72 hours). My working hypothesis is that ? T cells are required for the recruitment/generation of M2 macrophages after O3 exposure, and that this recruitment is required for resolution of injury. To test this hypothesis, ? T cell deficient mice (TCR-/-) will be exposed to subacute O3 and a time course for the recruitment of innate immune cells to both the bronchoalveolar lavage fluid and the lung tissue will assessed and compared to Wt mice. Additionally, cytokines and chemokines affected by the absence of ? T cells will be assessed and their respective roles in the recruitment will be determined in experiments where TCR-/- are reconstituted with ? T cells isolated from knockouts of the respective cytokines. Initial studies will focus on IL-17 and IP-10. Furthermore, resolution and repair in both Wt and TCR-/- mice will be compared, by exposing animals to either air or O3 for 72 hrs and then allowing them to recover. Mice will then be euthanized at a variety of time points and recovery will be assessed by examining alveolar/capillary permeability as well as apoptosis and proliferation of the epithelial lining. As macrophages have a large role in resolution in other models, we will also assess the phenotype of macrophages (M1 or M2) recruited/generated by O3 exposure and how the lack of ? T cells affects this recruitment. M2 macrophages are particularly involved in the removal of apoptotic cells. Our hypothesis is that IL-13 production by ? T cells is required for the generation of M2 macrophages after O3.
O3 is a common air pollutant that causes pulmonary morbidity and mortality. This study will define the role of ?? T cells in the resolution of injury and inflammation after O3 exposure. Understanding the cells and signals required for resolution of O3-induced injury may be important in understanding why some groups are more susceptible to O3 morbidity and mortality than others.
|Mathews, Joel A; Krishnamoorthy, Nandini; Kasahara, David I et al. (2018) Augmented Responses to Ozone in Obese Mice Require IL-17A and Gastrin-Releasing Peptide. Am J Respir Cell Mol Biol 58:341-351|
|Cho, Youngji; Abu-Ali, Galeb; Tashiro, Hiroki et al. (2018) The Microbiome Regulates Pulmonary Responses to Ozone in Mice. Am J Respir Cell Mol Biol 59:346-354|
|Kasahara, D I; Mathews, J A; Ninin, F M C et al. (2017) Role of ROCK2 in CD4+ cells in allergic airways responses in mice. Clin Exp Allergy 47:224-235|
|Mathews, Joel Andrew; Kasahara, David Itiro; Cho, Youngji et al. (2017) Effect of acute ozone exposure on the lung metabolomes of obese and lean mice. PLoS One 12:e0181017|
|Brand, Jeffrey D; Mathews, Joel A; Kasahara, David I et al. (2016) Regulation of IL-17A expression in mice following subacute ozone exposure. J Immunotoxicol 13:428-38|
|Rosenblum Lichtenstein, Jamie H; Molina, Ramon M; Donaghey, Thomas C et al. (2016) Repeated Mouse Lung Exposures to Stachybotrys chartarum Shift Immune Response from Type 1 to Type 2. Am J Respir Cell Mol Biol 55:521-531|
|Williams, Alison Suzanne; Mathews, Joel Andrew; Kasahara, David Itiro et al. (2015) Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-?. Am J Physiol Lung Cell Mol Physiol 308:L1168-77|
|Kasahara, David I; Mathews, Joel A; Park, Chan Y et al. (2015) ROCK insufficiency attenuates ozone-induced airway hyperresponsiveness in mice. Am J Physiol Lung Cell Mol Physiol 309:L736-46|
|Mathews, Joel A; Wurmbrand, Allison P; Ribeiro, Luiza et al. (2014) Induction of IL-17A Precedes Development of Airway Hyperresponsiveness during Diet-Induced Obesity and Correlates with Complement Factor D. Front Immunol 5:440|
|Mathews, Joel A; Williams, Alison S; Brand, Jeffrey D et al. (2014) ?? T cells are required for pulmonary IL-17A expression after ozone exposure in mice: role of TNF?. PLoS One 9:e97707|
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