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Abstract
Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), chronic obstructive pulmonary disease and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. In particular, excess monocyte mobilization during AIE and their persistence in the lung have been linked to poor disease outcome. The etiology of AIEs remains quite uncertain, but environmental exposure and genetic predisposition/mutations have been identified as two contributing factors. Guided by clinical evidence, we have developed a mutant model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine substitution at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [SFTPC]. With this toolbox at hand, the present work investigates the role of peripheral monocytes during the initiation and progression of AIE-PF. Genetic ablation of CCR2+ monocytes (SP-CI73TCCR2KO) resulted in improved lung histology, mouse survival, and reduced inflammation compared to SP-CI73TCCR2WT cohorts. FACS analysis of CD11b+CD64-Ly6Chi monocytes isolated 3 d and 14 d after SP-CI73T induced injury reveals dynamic transcriptional changes associated with “Innate Immunity’ and ‘Extracellular Matrix Organization’ signaling. While immunohistochemical and in situ hybridization analysis revealed comparable levels of tgfb1 mRNA expression localized primarily in parenchymal cells found nearby foci of injury we found reduced effector cell activation (C1q, iNOS, Arg1) in SP-CI73TCCR2KO lungs as well as partial colocalization of tgfb1 mRNA expression in Arg1+ cells. These results provide a detailed picture of the role of resident macrophages and recruited monocytes in the context of AIE-PF driven by alveolar epithelial dysfunction.
Highlights
Pulmonary fibrosis (PF) is a devastating degenerating disease characterized by failure to properly resolve inflammation, heterogeneous disruption of alveolar and bronchiolar architecture, and irreversible scarring [1,2,3]
We have previously shown that lung injury generated by induction of mutant SP-CI73T expression is accompanied by dynamic changes in SigF+CD11bint resident alveolar macrophage and CD11b+Ly6Chi infiltrating monocyte mobilization and activation [27]
We used comparable gating strategy to sort CD11b+Ly6Chi inflammatory monocytes from collagenase digested tissue 3 d and 14 d post induction, times coordinated with initiation and peak of inflammatory exacerbations
Summary
Pulmonary fibrosis (PF) is a devastating degenerating disease characterized by failure to properly resolve inflammation, heterogeneous disruption of alveolar and bronchiolar architecture, and irreversible scarring [1,2,3]. Despite the intrinsic ability of the lung parenchyma to withstand repeated bouts of injury, persistent and widespread stress induced by endogenous (functional mutations) and/or exogenous (infection, toxicant exposure) sources promotes aberrant epithelial-immune and epithelial-mesenchymal communication In this context, inflammation has been widely studied as an essential aspect of fibrogenic scarring and PF progression, with so called “acute inflammatory exacerbations” (AIE) strongly linked to lung function decline and mortality [4,5,6]. Leveraging chemical-induced fibrosis (i.e., bleomycin, asbestos) and innovative lineage tracing systems defined peripheral monocytes as a dynamic mixture of populations that has the capacity to differentiate into alveolar macrophage-like cells, yet remains incompetent in their ability to terminate/resolve inflammation, a function central to “true” resident alveolar macrophages [9, 14] With this in mind, it is essential to comprehend monocyte biology to fully appreciate their role in injury resolution and tissue remodeling occurring during AIE-PF [9, 20]
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