Chronic interstitial lung disease is observed in a variety of disorders, including infectious diseases, autoimmune disorders of connective tissue, and disorders where the etiology is unknown, such as idiopathic pulmonary fibrosis. While the etiology and mechanism of progression of many of these lung disorders are not known, the exacerbated progression of the disease may be dictated by the host responding to a subsequent pathogen superimposed on the initial etiologic agent. This """"""""second hit"""""""" triggers a dynamic interaction in the lung between the inciting agent, immune cells, and structural cells of the lung, culminating in fibroblast activation, proliferation and fibrosis. Understanding the mechanisms responsible for the exacerbation and progression of lung disease chronicity and fibrosis are the broad, long-term objectives of this application. We hypothesize that the host's response to a persistent etiologic agent may predispose lung tissue to an environment of reparative and immunoregulatory cytokines, placing the lungs at risk for a viral infection, which mechanistically contributes to disease chronicity by maintaining a unique cytokine phenotype, altering dendritic cell function, and driving fibroblast activation. We have designed experiments to test this hypothesis and determine if the progression and maintenance of chronic lung inflammation are infuenced by the cytokine phenotype and the host's response to a subsequent viral pathogen superimposed on the initial etiologic agent, constituting a """"""""two hit"""""""" mechanism for disease progression. We will focus on mechanisms which lead to a minimally fibrotic lung lesion, induced by type 1 cytokines, versus a fibrotic response, induced by type 2 cytokines, and determine their impact on a subsequent challenging with murine gammaherpesvirus (MHV68).
Our specific Aims i nclude: 1) To assess the mechanism(s) whereby MHV68 infection alone or superimposed on a polarized cytokine phenotype alters the host response and subsequent lung pathology in experimental models of chronic lung inflammation;2) To determine the mechanistic contribution of an MHV68-derived gene product on the evolving chronic lung pathology associated with a type 1 or type 2 cytokine tissue phenotype; and 3) To assess the mechanistic contribution of dendritic cell subsets during MHV68 infection to the chronicity and fibrosis of the lung response in animals with developing type 1 or type 2 cytokine phenotypes.
Chronic lung disease is an increasing common clinical disorder caused by many know and unknown (idiopathic) agents. The clinical manifestations of many of these chronic lung diseases are likely the consequences of the host response to an initial agent followed by pulmonary tissue injury, progressive deterioration of lung function, and increase susceptibility to pathogen-induced exacerbations. These factors often make these diseases not well understood with difficult and unrewarding therapies. We have experimentally modeled chronic long disease and will study the underlying mechanisms that we believe support these disorders.
|Schaller, Matthew; Ito, Toshihiro; Allen, Ronald M et al. (2015) Epigenetic regulation of IL-12-dependent T cell proliferation. J Leukoc Biol 98:601-13|
|Ueha, R; Mukherjee, S; Ueha, S et al. (2014) Viral disruption of olfactory progenitors is exacerbated in allergic mice. Int Immunopharmacol 22:242-7|
|Shibata, Takehiko; Habiel, David M; Coelho, Ana L et al. (2014) Axl receptor blockade ameliorates pulmonary pathology resulting from primary viral infection and viral exacerbation of asthma. J Immunol 192:3569-81|
|Cavassani, Karen A; Moreira, Ana Paula; Habiel, David et al. (2013) Toll like receptor 3 plays a critical role in the progression and severity of acetaminophen-induced hepatotoxicity. PLoS One 8:e65899|
|Ito, Toshihiro; Connett, Judith M; Kunkel, Steven L et al. (2012) Notch system in the linkage of innate and adaptive immunity. J Leukoc Biol 92:59-65|
|Shimizu-Hirota, Ryoko; Xiong, Wanfen; Baxter, B Timothy et al. (2012) MT1-MMP regulates the PI3KÎ´Â·Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev 26:395-413|
|Frantz, Fabiani Gai; Ito, Toshihiro; Cavassani, Karen Angelica et al. (2011) Therapeutic DNA vaccine reduces schistosoma mansoni-induced tissue damage through cytokine balance and decreased migration of myofibroblasts. Am J Pathol 179:223-9|
|Carson 4th, William F; Kunkel, Steven L (2011) Monocytes to functional dendritic cells is often a bridge too far for cancer therapy. Transl Res 158:197-9|
|Ito, Toshihiro; Carson 4th, William F; Cavassani, Karen A et al. (2011) CCR6 as a mediator of immunity in the lung and gut. Exp Cell Res 317:613-9|
|Carson, William F; Cavassani, Karen A; Dou, Yali et al. (2011) Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics 6:273-83|
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