Early-stage idiopathic pulmonary fibrosis is characterized by bronchoalveolar accumulation of SPP1+ macrophages
Patients affected by idiopathic pulmonary fibrosis (IPF), a progressive chronic and eventually fatal lung disease with unknown causes, suffer from delayed diagnosis due to the lack of predictive markers for disease development. Prior studies focused on the cellular and transcriptomic changes found in lung tissue during established, often terminal, lung disease. In clinical routine, bronchoscopy is applied for diagnosis and staging of suspected IPF affected individuals, thus providing us with a clinically applicable window, to study the cellular and transcriptional changes within affected individuals. Here we study a patient collective consisting of 11 IPF affected individuals and 11 healthy controls. We investigate their single cell transcriptomic profile alongside their cellular surface phenotype of alveolar-resident immune cells. Single cell transcriptional analysis reveals early accumulation of SPP1+ macrophages (SPP1+M?) within the alveolar space as an early cellular sign of IPF, in the absence of a decline in lung function. Early-stage IPF accumulated SPP1+M? were characterized by high expression of lipid storage and handling genes, accumulation of intracellular cholesterol and expression of proinflammatory cytokine expression. In silico developmental trajectory analysis revealed that SPP1+M? are likely derived from monocytes. Finally to confirm the clinical diagnostic value of SPP1+ M? we developed a flow cytometry panel to rapidly identify and test for the presence of SPP1+ M? in bronchoalveolar lavage samples and confirm our observation in an independent validation cohort. Taken together, we show that SPP1+ M? are associated with early IPF pathogenesis in the absence of an obvious decline in lung function, thus providing a clinically valuable markers for easy diagnosis of early IPF in clinical practice. Overall design: Cells isolated from BALF samples from patients or control subjects were analyzed by scRNA sequencing.