Targeted delivery of doxycycline with nanoparticles mitigates cytokine
storm and reduces immune cell infiltration in LPS mediated lung
inflammation.
Abstract
Background and Purpose: Cytokine storm invoked during acute and chronic
lung injury promotes alveolar damage and remodeling. The current study
shows that degraded elastin-targeted nanoparticles releasing doxycycline
(Doxy NPs) are potent in mitigating cytokines storm, migration of immune
cells in the lungs, and inhibiting inflammasome pathways in the LPS
mouse model. Experimental Approach: Cytokine storm and lung injury were
induced using LPS and elastase in C57BL/6 mice (rodent model for
emphysema). The mice were then treated with I.V. Doxy NPs, blank NPs, or
Doxy a day before LPS administration. Cytokine levels, immune cell
population, and MMP activity were analyzed in BALF 4 hours after LPS
administration. Additionally, gene expression of IL-6, IL-1beta, MCP-1,
NLRP3, Caspase 1, and MMPs were investigated in alveolar cells on day
three after LPS administration. Key Results: Doxycycline NPs but not
Doxycycline significantly decreased IL-6, TNF-α, and IL-23 and were
significantly more effective in decreasing the percentage of immune
cells in the BALF. This is the first in-vivo study to demonstrate that
Doxycycline can effectively inhibit lung inflammasome pathways.
Conclusion and Implications: IV administration of elastin antibody
conjugated Doxycycline-loaded albumin Nps can effectively modulate the
local immune environment in the lungs, which is not achieved by IV
Doxycycline even at a 100-fold higher dose. This novel method of drug
delivery can effectively lead to the repurposing of traditional
Doxycycline as a potential adjunct treatment for managing the cytokine
storm in the lungs in COPD and viral infections.