Biology subjects

Booth, H. L.

Publications and source records attributed to Booth, H. L..

3 recordsLinked to original sources

bioRxiv2020

Platelet counts predict prognosis in IPF, but are not the main source of pulmonary TGFβ1

Transforming growth factor-{beta}1 (TGF{beta}1) is the key pro-fibrotic cytokine implicated in the interstitial lung diseases (ILD), including idiopathic pulmonary fibrosis (IPF), but the primary source of TGF{beta}1 in these diseases is unknown. Platelets have abundant TGF{beta}1 stores, however their role in IPF is ill-defined. We sought to investigate whether platelets or platelet-derived TGF{beta}1 mediate IPF disease progression. ILD/IPF and non-ILD patients were recruited to determine platelet reactivity and followed for mortality. To study whether platelet-derived TGF{beta}1 modulates pulmonary fibrosis, mice with a targeted deletion of TGF{beta}1 in megakaryocytes and platelets (TGF{beta}1fl/fl.PF4-Cre) were used in the bleomycin-induced PF model. We found a significantly higher mortality in IPF patients with elevated platelet counts, along with significantly increased platelets, neutrophils, TGF{beta}1 and CCL5 in the lung and bronchoalveolar lavage (BAL) of ILD patients. Despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation or fibrosis were significantly different between TGF{beta}1fl/fl.PF4-Cre and control mice. Our results demonstrate for the first-time that platelet-derived TGF{beta}1 is redundant in driving pulmonary fibrosis in an animal model. However, platelets can predict mortality in IPF implicating other platelet-derived mediators, such as CCL5, in promoting human IPF disease.

cell biology↗

bioRxiv2020

Identification of a novel HIF-1α-αMβ2 Integrin-NETosis axis in fibrotic interstitial lung disease

Neutrophilic inflammation correlates with mortality in fibrotic interstitial lung disease (ILD) however, the underlying mechanisms remain unclear. We aimed to determine whether aberrant neutrophil activation is a feature of ILD and the relative role of hypoxia. We used lung biopsies and bronchoalveolar lavage (BAL) from ILD patients to investigate the extent of hypoxia and neutrophil activation in lungs of patients with ILD. We complemented these findings with ex vivo functional studies of neutrophils from healthy volunteers to determine the effects of hypoxia. We demonstrate for the first time HIF-1 staining in neutrophils and endothelial cells in ILD lung biopsies. Hypoxia enhanced both spontaneous and phorbol 12-myristate 13-acetate (PMA)-induced neutrophil extracellular trap (NET) release (NETosis), neutrophil adhesion, and trans-endothelial migration. Hypoxia also increased neutrophil expression of the M and X integrin subunits. Interestingly, NETosis was induced by M{beta}2 integrin activation and prevented by cation chelation. Finally, NETs were demonstrated in the BAL from ILD patients, and quantification showed significantly increased cell-free DNA content and MPO-citrullinated histone H3 complexes in ILD patients compared to non-ILD controls. Our work indicates that HIF-1 upregulation may augment neutrophil recruitment and activation within the lung interstitium through activation of {beta}2 integrins. Our results identify a novel HIF-1-Integrin-NETosis axis for future exploration in therapeutic approaches to fibrotic ILD.

immunology↗

bioRxiv2019

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

RationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.\n\nObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.\n\nMethods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.\n\nMain resultsWe identified and replicated three new genome-wide significant (P<5x10-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.\n\nConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

genomics↗