Resolution of experimental malaria-associated acute respiratory distress syndrome is Alox12 independent and shows residual inflammation.

Abstract

Background: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a lung complication affecting 5-25% of adults with severe malaria and has a mortality rate of ~ 40% despite mechanical ventilation. Effective recovery requires the resolution of inflammation, an active process involving pathogen clearance, suppression of inflammation, and tissue repair. While antimalarial drugs eliminate the parasite, they do not adequately promote resolution.

Methods: Using Nanostring nCounter technology, 840 inflammation- and metabolism-related genes were profiled in lung tissue from Plasmodium berghei NK65-infected mice, comparing untreated and antimalarial-treated groups to identify gene signatures specific to pathology and resolution.

Results: Among the resolution-specific genes, Alox12, encoding 12-lipoxygenase, was identified as a key regulator of specialized pro-resolving mediators (SPMs). However, functional studies targeting the 12-lipoxygenase pathway with the ML355 inhibitor or with Maresin Conjugate in Tissue Regeneration 1 supplementation did not affect survival or resolution outcomes. Further bioinformatic analysis of the Nanostring data revealed persistent T cell-driven inflammation, partial reduction in JAK/STAT signalling, altered chemokine expression and incomplete metabolic recovery during the resolution phase of MA-ARDS.

Conclusions: These findings suggest that while Nanostring profiling reveals critical processes in MA-ARDS resolution, targeting late-stage resolution alone by modulating SPM production is insufficient. This suggests that more effective, multi-targeted adjunctive therapies, alongside antimalarial drugs, may be required to improve survival and resolution upon MA-ARDS.