Acute Lung Injury (ALI) is a life-threatening disorder underpinned by dysregulated inflammatory cascades, with resultant injury to lung architecture. Currently, provision of supportive care represents the mainstay of treatment for ALI and novel anti-inflammatory therapeutic strategies are urgently required. We have developed a polymeric nanoconstruct surface-functionalised with sialic acid targeting moieties (SNP), exploiting the anti-inflammatory effects arising from the targeted engagement of Siglec-E receptors on activated macrophages, with potential therapeutic utility in ALI.

Polylactic-co-glycolic acid (PLGA) nanoparticles of uniform size distribution (approximately 150nm in diameter) were synthesised in accordance with a salting-out formulation. Intratracheal instillation of 20μg lipopolysaccharide (LPS) was utilised as a model of ALI in C57BL/6 mice, co-administered with 1μg SNP or non-functionalised nanoparticles (NP). Bronchoalveolar lavage (BALF) samples were collected 24 hours after treatment for analysis by enzyme-linked immunosorbent assay (ELISA).

As exemplified in Figure 1., intratracheal instillation of SNP significantly attenuated BALF levels of pro-inflammatory TNFα and IL-6 cytokines, in addition to the neutrophil chemoattractant KC. Moreover, BALF differential cell counts revealed a decrease in neutrophil numbers upon treatment with SNP under LPS-induced pro-inflammatory conditions. Further analyses addressing the therapeutic utility of SNP have been undertaken, including lung wet/dry ratios, histology and toxicological evaluation, with promising outcomes.

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Abstract S95 Figure 1.

Therapeutic efficacy of SNP in a murine model of LPS-induced ALI (* p<0.05, **p<0.001, ***p<0.001 compared to LPS control, as established by one-way ANOVA and Tuley post-hoc test).

This research clearly demonstrates the ability of SNP to diminish the inflammatory response in a murine model of LPS-induced ALI. Considering that chemoattractants and cytokines are key mediators in the pathogenesis of ALI, these results substantiate the credibility of this nanoscaffold as a therapy for ALI. Ultimately, we aim to progress this modality to a human setting, specifically analysing its effects on alveolar macrophages isolated from human volunteers, before advancing to a human ex vivo lung perfusion model.