The IL-1 type 1 receptor is required for the development of LPS-induced airways disease

Background

The contribution of IL-1β signaling through the IL-1 type 1 receptor (IL-1R1) to the development of persistent LPS-induced airway disease has not been investigated.

Objective

To determine the importance of signaling through the IL-1 type 1 receptor in the development of LPS-induced airway disease.

Methods

We exposed IL-1R1–deficient (C57BL/6^{IL-1RI–/–}) mice to an aerosol of LPS or filtered air for 1 day, 1 week, or 4 weeks.

Results

After 4 weeks of LPS inhalation, C57BL/6^{IL-1RI–/–} mice failed to develop significant submucosal thickening, whereas C57BL/6 mice had significantly thickened submucosa in small, medium, and large airways compared with those of unexposed control mice. Cell proliferation in the airways of both the 1-week and 4-week LPS-exposed C57BL/6^{IL-1RI–/–} mice was significantly reduced compared with LPS-exposed C57BL/6 mice. mRNA for type III α-3 procollagen was significantly elevated over baseline in C57BL/6 yet remained unchanged compared with baseline in C57BL/6^{IL-1RI–/–} mice after 1 week or 4 weeks of LPS inhalation. mRNA for tissue inhibitor of metalloprotease 1 in C57BL/6 mice in the 1-week and 4-week groups was significantly elevated over both control mice and C57BL/6^{IL-1RI–/–} mice.

Conclusion

These data support the hypothesis that signaling through the IL-1 receptor modulates extracellular matrix homeostasis in response to inhaled LPS.

Clinical implications

Attenuating IL-1R1–mediated signaling might be an effective therapy against the development of airway remodeling in chronic inflammatory diseases.

Key words: LPS, endotoxin, airway disease, IL-1, IL-1 receptor, airway remodeling

Abbreviations used: BAL, Bronchoalveolar lavage, BrdU, Bromo-deoxy-uridine, fMLP, Formyl-Met-Leu-Phe, IL-1R1, IL-1 type I receptor, NF-κB, Nuclear factor-κB, PAI, Plasminogen activator inhibitor, PMA, Phorbol myristate acetate, TIMP-1, Tissue inhibitor of metalloprotease 1, TLR4, Toll-like receptor 4, uPAR, Urokinase plasminogen activator receptor