Abstract
Abstract Neutrophil aging is the process through which neutrophils released from the bone marrow into circulation acquire specific phenotypic and functional changes over time. After neutrophils age in circulation, they return to the bone marrow or other organs for clearance. Aged neutrophils are highly proinflammatory and can potentially contribute to tissue injury if their return to and clearance within the bone marrow is dysregulated. We have found that the development of pulmonary fibrosis in mice is associated with decreased numbers of aged neutrophils within the bone marrow compared to non-fibrotic mice 21 days after induction of fibrosis, indicating that neutrophils are not returning to the bone marrow for clearance after aging in circulation. Indeed, we observed a corresponding increase in the numbers of aged neutrophils in peripheral blood and bronchioalveolar fluid (BALF) of fibrotic mice compared to non-fibrotic mice, supporting the idea that pulmonary fibrosis prevents neutrophil migration back to the bone marrow after aging. Pulmonary fibrosis is a disease characterized by aberrant wound healing and lung and vascular injury. In accordance with this, we have observed increased levels of extracellular DNA and neutrophil elastase in plasma and BALF of mice 21 days after induction of fibrosis. These products are released in high levels by aged neutrophils during the formation of neutrophil extracellular traps, suggesting that aberrant aged neutrophil behavior may contribute to lung and vascular injury in pulmonary fibrosis. Our study seeks to understand the role of neutrophils in fibrotic disease progression by evaluating how fibrosis may alter the trafficking of aged, highly proinflammatory neutrophils. Supported by grants from NIH (R35 HL144481, F31 HL152509) and the Scleroderma Foundation (Arnold Postlethwaite, M.D. Memorial Pre-Doctoral Summer Fellowship Award)
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