E-Poster with pre-recorded video presentation Lorne Infection and Immunity 2021

Nanoparticle-mediated pulmonary delivery of the peptide hormone relaxin abrogates chronic allergic airways disease (#300)

Amlan Chakraborty 1 , Anita Pinar 1 , Simon Royce 1 , Cordelia Selomulya 2 , Chrishan Samuel 1
  1. Monash Biomedicine Discovery Institute and Pharmacology, Monash University, Clayton, Victoria, Australia
  2. Chemical Engineering, UNSW Sydney, Sydney, NSW, Australia

Chronic allergic airways disease (AAD) is a hallmark T Helper type 2 (TH2) disease characterised by airway inflammation (AI), airway remodeling (AWR) and airway hyperresponsiveness (AHR). Current treatments of AAD mainly focus on targeting AI and its contribution AHR, with the use of corticosteroids. However, there are no therapies for the direct treatment of AWR, that can contribute to AHR independently of AI, and which contributes to corticosteroid resistance. The acute heart failure drug, serelaxin (recombinant human gene-2 relaxin/RLX), has been shown to ameliorate lung fibrosis and related AHR/lung dysfunction in various pre-clinical disease models1,2, but requires continuous systemic delivery or daily intranasal administration3. We developed serelaxin-conjugated biodegradable nanoparticles (NP-RLX) and demonstrated for the first time the use of these particles as translational therapies for the treatment of AAD. Intranasally-delivered NP-RLX was primarily taken up by alveolar macrophages. Characterisation of inflammatory myeloid cell influx in the lung demonstrated the necessity of CD206 (mannose receptor) and CD68 (a pan-macrophage/dendritic cell) markers for uptake of NP-RLX in mitigating these effects. Furthermore, intranasally-delivered NP-RLX was found to abrogate AI by reducing the levels of pro-inflammatory cytokines (specifically IL-1β) and the influx of pro-inflammatory cells such as alveolar macrophages and eosinophils. NP-RLX also reduced several features of AWR by reducing the TGF-β1/IL-1β axis at the level of phosphorylated Smad2, as well as AHR. These findings demonstrate the therapeutic efficacy of nanoparticle-conjugated RLX in the airways/lung and represent a clinically translatable and effective strategy for the treatment of chronic AAD, which present with several features of human asthma.

  1. 1. Royce, S.G. et al. Relaxin reverses airway remodeling and airway dysfunction in allergic airways disease. Endocrinology 150, 2692-2699 (2009).
  2. 2. Patel, K.P., Giraud, A.S., Samuel, C.S. & Royce, S.G. Combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment for allergic airways disease. Br J Pharmacol 173, 2016-2029 (2016).
  3. 3. Royce, S.G. et al. Intranasally administered serelaxin abrogates airway remodelling and attenuates airway hyperresponsiveness in allergic airways disease. Clin Exp Allergy 44, 1399-1408 (2014).