Pentosan polysulfate sodium prevents functional decline in chikungunya infected mice by modulating growth factor signalling and lymphocyte activation

Abstract

Chikungunya virus (CHIKV) is an arthropod-borne virus that causes large outbreaks world-wide leaving millions of people with severe and debilitating arthritis. Interestingly, clinical presentation of CHIKV arthritides have many overlapping features with rheumatoid arthritis including cellular and cytokine pathways that lead to disease development and progression. Currently, there are no specific treatments or vaccines available to treat CHIKV infections therefore advocating the need for the development of novel therapeutic strategies to treat CHIKV rheumatic disease. Herein, we provide an in-depth analysis of an efficacious new treatment for CHIKV arthritis with a semi-synthetic sulphated polysaccharide, Pentosan Polysulfate Sodium (PPS). Mice treated with PPS showed significant functional improvement as measured by grip strength and a reduction in hind limb foot swelling. Histological analysis of the affected joint showed local inflammation was reduced as seen by a decreased number of infiltrating immune cells. Additionally, joint cartilage was protected as demonstrated by increased proteoglycan staining. Using a multiplex-immunoassay system, we also showed that at peak disease, PPS treatment led to a systemic reduction of the chemokines CXCL1, CCL2 (MCP-1), CCL7 (MCP-3) and CCL12 (MCP-5) which may be associated with the reduction in cellular infiltrates. Further characterisation of the local effect of PPS in its action to reduce joint and muscle inflammation was performed using NanoString™ technology. Results showed that PPS altered the local expression of key functional genes characterised for their involvement in growth factor signalling and lymphocyte activation. Overall, this study shows that PPS is a promising treatment for alphaviral arthritis by reducing inflammation and protecting joint integrity.

The effect of pentosan polysulfate sodium for improving dyslipidaemia and knee pain in people with knee osteoarthritis: A pilot study

“…Due to a previous report of potentially low oral bioavailability [ 22 ], we chose a relatively large oral dose to enhance the bioavailability. Animal studies show that PPS may reduce joint inflammation by altering the local expression of key functional genes characterised for their involvement in growth factor signalling and lymphocyte activation as well as its positive effect on the anti-inflammatory IL-35 level [ 23 , 24 ].…”

Anti-inflammatory actions of Pentosan polysulfate sodium in a mouse model of influenza virus A/PR8/34-induced pulmonary inflammation

“…Tissues were processed for paraffin embedding and non-consecutive 5 µm sections (25-30 µm apart starting at ~500 µm depth) were performed and stained with either haematoxylin and eosin (H&E) stain for cell infiltration or Masson Trichrome (MT) stain for detection of collagen. Slides were scanned using a Leica Aperio AT2 (Leica Biosystems) and images processed using QuPath software ( 21 ). For H&E-stained slides, nuclei were detected as individual objects using NucleiCount v9 algorithm on QuPath.…”

“…The oral formulation of PPS is an approved treatment for interstitial cystitis and bladder pain syndrome in Europe and the United States for over twenty years ( 18 ). The multiple mechanisms of action of PPS have provided the scientific rationale for repurposing the drug in other indications with unmet medical needs such as osteoarthritis ( 19 ) and alphavirus-induced arthralgia ( 20 , 21 ). As PPS was demonstrated to be effective in a guinea pig model of allergen-induced rhinitis via its actions as an inhibitor of the Th2 cytokines IL-4, IL-5 and IL-13 ( 22 ), we extended our investigations to explore the effects of PPS in acute inflammation mediated by viral infection of the lung.…”

Pentosan Polysulfate Affords Pleotropic Protection to Multiple Cells and Tissues

“…In the CHIKV-infected mice, the functional decline was prevented by modulation of growth factor signaling and lymphocyte activation. PPS treatment led to a systemic reduction of the chemokines CXCL1, CCL2 (MCP-1), CCL7 (MCP-3) and CCL12 (MCP-5), all of which are involved with the reduction in cellular infiltrates, less inflammation and less joint swelling [ 271 ].…”