{Reference Type}: Journal Article
{Title}: The protein disulfide isomerase A3 and osteopontin axis promotes influenza-induced lung remodelling.
{Author}: Kumar A;Mark ZF;Carbajal MP;DeLima DS;Chamberlain N;Walzer J;Ruban M;Chandrasekaran R;Daphtary N;Aliyeva M;Poynter ME;Janssen-Heininger YMW;Bates JH;Alcorn JF;Britto CJ;Dela Cruz CS;Jegga AG;Anathy V;
{Journal}: Br J Pharmacol
{Volume}: 0
{Issue}: 0
{Year}: 2024 Aug 8
{Factor}: 9.473
{DOI}: 10.1111/bph.16511
{Abstract}: <B>OBJECTIVE: </B>Fibrotic lung remodelling after a respiratory viral infection represents a debilitating clinical sequela. Studying or managing viral-fibrotic sequela remains challenging, due to limited therapeutic options and lack of understanding of mechanisms. This study determined whether protein disulfide isomerase A3 (PDIA3) and secreted phosphoprotein 1 (SPP1), which are associated with pulmonary fibrosis, can promote influenza-induced lung fibrotic remodelling and whether inhibition of PDIA3 or SPP1 can resolve viral-mediated fibrotic remodelling.<BR><B>METHODS: </B>A retrospective analysis of TriNetX data sets was conducted. Serum from healthy controls and influenza A virus (IAV)-infected patients was analysed. An inhibitor of PDIA3, punicalagin, and a neutralizing antibody for SPP1 were administered in mice. Macrophage cells treated with macrophage colony-stimulating factor (M-CSF) were used as a cell culture model.<BR><B>RESULTS: </B>The TriNetX data set showed an increase in lung fibrosis and decline in lung function in flu-infected acute respiratory distress syndrome (ARDS) patients compared with non-ARDS patients. Serum samples revealed a significant increase in SPP1 and PDIA3 in influenza-infected patients. Lung PDIA3 and SPP1 expression increased following viral infection in mouse models. Punicalagin administration 2 weeks after IAV infection in mice caused a significant decrease in lung fibrosis and improved oxygen saturation. Administration of neutralizing SPP1 antibody decreased lung fibrosis. Inhibition of PDIA3 decreased SPP1secretion from macrophages, in association with diminished disulfide bonds in SPP1.<BR><B>CONCLUSIONS: </B>The PDIA3-SPP1 axis promotes post-influenza lung fibrosis in mice and that pharmacological inhibition of PDIA3 or SPP1 can treat virus-induced lung fibrotic sequela.