SPLUNC1/BPIFA1 Restrains Neutrophil-Dominant Inflammation and Coordinated Inflammatory Gene Programs During LPS-Induced Lung Injury.

Abstract

Acute lung injury (ALI) is characterized by alveolar-capillary barrier disruption, increased pulmonary permeability, impaired gas exchange, and inflammation. Lipopolysaccharide (LPS), a potent microbial trigger of inflammation, is widely used to model ALI. Short palate, lung, and nasal epithelial clone 1 (SPLUNC1), also known as BPIFA1, is an abundant surfactant-like protein secreted by the airway epithelium with antimicrobial and immunomodulatory functions. However, its role in endotoxin-induced lung injury remains incompletely understood. We compared pulmonary responses to LPS in wild-type and SPLUNC1/BPIFA1-knockout mice. Mice received intranasal PBS or 5 μg LPS were evaluated 24 h later by bronchoalveolar lavage, histology, cytospin, flow cytometry, qPCR, ELISA, and whole-lung RNA sequencing. Compared with WT mice, LPS-challenged KO mice exhibited greater inflammatory-cell accumulation, enhanced neutrophil recruitment, increased cytokine and chemokine expression, and greater histologic lung injury. Transcriptomic analyses showed preferential activation of TNFα/NF-κB, IL-6-JAK-STAT3, complement, cytokine/chemokine, myeloid/neutrophil, and stress-response in KO lungs. These findings identify SPLUNC1/BPIFA1 as an epithelial-derived regulator that restrains endotoxin-induced inflammatory signaling, neutrophil recruitment, and tissue injury. Collectively, these results support a protective role for SPLUNC1/BPIFA1 in acute pulmonary inflammation and provide a rationale for investigating SPLUNC1/BPIFA1 augmentation to mitigate ALI. Further studies evaluating SPLUNC1-based interventions in preclinical models are warranted.