The lung is exposed to many environmental challenges throughout life, and further information is needed about secreted moieties that serve to sustain homeostasis. We generated mice that lack an epithelial enzyme necessary to degrade environmental polysaccharides widely prevalent in the environment. After polysaccharide challenge, these mice sustain prolonged lung inflammation associated with activation of Group 2 innate lymphoid cells (ILC2s) and lung gamma-delta T cells that release cytokines, including IL-5 and IL-13, and IL-17, respectively. The resultant inflammatory infiltrate including neutrophils and eosinophils, cause lung damage that can be overcome when epithelial enzymatic activity is restored. Unexpectedly, these knockout mice developed spontaneous lung inflammation over 6-9 months, even when maintained in a pathogen-free facility. Inflammation included fibrosis, most prominent around medium airways, and was characterized by enhanced tissue cellularity and increased lung collagen. As such, these mice provide a spontaneous model for pulmonary fibrosis due to activation of innate lung lymphoid cells and over-expression of IL-13 and IL-7, two cytokines previously implicated in prior models of provoked organ and tissue fibrosis. We have generated a number of genetically marked reporter mice to follow the relevant cells and cytokines, which will be used to unravel the mechanisms underlying this fibrosing phenotype. The grant proposes to study the lung phenotype in three Specific Aims. 1. To establish the role for lung ILC2 cells to determine whether these cells and IL-13 play an injury-promoting or injury-attenuating role. 2. To establish the role for lung gamma-delta cells to determine the role these cells and IL-17 play in the phenotype. 3. To establish the mechanism by which the lung disposes of insoluble environmental polysaccharides. Humans contain the same enzyme in robust amounts in bronchoalveolar lavage, suggesting evolutionary conservation of this pathway for lung homeostasis. Our studies may have relevance to understanding modifiers of chronic fibrosing syndromes of humans, such as idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis, conditions for which further pathogenetic insights are needed.
This grant will study a model of spontaneous lung fibrosis in mice that lack a lung enzyme normally present in airway secretions of mice and humans. This enzyme degrades a component of fungi and insects that is widespread in the environment. Understanding the mechanisms by which this enzyme preserves lung function may be important in chronic human lung diseases complicated by fibrosis.
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