Anti-Fibrotic Effect of SDF-1ß Overexpression in Bleomycin-Injured Rat Lung.

Rational: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease and is associated with high mortality due to a lack of effective treatment. Excessive deposition of the extracellular matrix by activated myofibroblasts in the alveolar space leads to scar formation that hinders gas exchange. Therefore, selectively removing activated myofibroblasts with the aim to repair and remodel fibrotic lungs is a promising approach. Stromal-derived growth factor (SDF-1) is known to stimulate cellular signals which attract stem cells to the site of injury for tissue repair and remodeling. Here, we investigate the effect of overexpression of SDF-1ß on lung structure using the bleomycin-injured rat lung model. Methods: Intratracheal administration of bleomycin was performed in adult male rats (F344). Seven days later, in vivo electroporation-mediated gene transfer of either SDF-1ß or the empty vector was performed. Animals were sacrificed seven days after gene transfer and histology, design-based stereology, flow cytometry, and collagen measurement were performed on the tissue collected. For in vitro experiments, lung fibroblasts obtained from IPF patients were used. Results: Seven days after SDF-1ß gene transfer to bleomycin-injured rat lungs, reduced total collagen, reduced collagen fibrils, improved histology and induced apoptosis of myofibroblasts were observed. Furthermore, it was revealed that TNF-α mediates SDF-1ß-induced apoptosis of myofibroblasts; moreover, SDF-1ß overexpression increased alveolar epithelial cell numbers and proliferation in vivo and also induced their migration in vitro. Conclusions: Our study demonstrates a new antifibrotic mechanism of SDF-1ß overexpression and suggests SDF-1ß as a potential new approach for the treatment of lung fibrosis.

Basal-Like Cell-Conditioned Medium Exerts Anti-Fibrotic Effects In Vitro and In Vivo.

In idiopathic pulmonary fibrosis (IPF), basal-like cells are atypically present in the alveolar region, where they may affect adjacent stromal cells by paracrine mechanisms. We here aimed to confirm the presence of basal-like cells in peripheral IPF lung tissue in vivo, to culture and characterize the cells in vitro, and to investigate their paracrine effects on IPF fibroblasts in vitro and in bleomycin-injured rats in vivo. Basal-like cells are mainly localized in areas of pathological bronchiolization or honeycomb cysts in peripheral IPF lung tissue. Single-cell RNA sequencing (scRNA-seq) demonstrated an overall homogeneity, the expression of the basal cell markers cytokeratin KRT5 and KRT17, and close transcriptomic similarities to basal cells in the majority of cells cultured in vitro. Basal-like cells secreted significant levels of prostaglandin E2 (PGE2), and their conditioned medium (CM) inhibited alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1) and upregulated matrix metalloproteinase-1 (MMP-1) and hepatocyte growth factor (HGF) by IPF fibroblasts in vitro. The instillation of CM in bleomycin-injured rat lungs resulted in reduced collagen content, improved lung architecture, and reduced α-SMA-positive cells. Our data suggested that basal-like cells may limit aberrant fibroblast activation and differentiation in IPF through paracrine mechanisms.

Predictors for delayed antibiotic administration among bacteraemic patients in the Emergency Department: Differences between medical and surgical interns.

BACKGROUND: Bloodstream infections (BSIs) have been associated with high mortality. The aim of the study was to identify predictors of early (within 3 hours from triage) administration of first antibiotic dose among patients evaluated in the Emergency Department (ED) with BSI and their role in mortality. MATERIALS AND METHODS: All adult patients with BSI at the ED of the Hospital of Jura, Switzerland during a 3 year period (July 2014 to June 2017) were included. RESULTS: Among 364 BSI, the most common sites of infection were urinary tract (39.6% of BSIs), lower respiratory tract (15.4%), intra-abdominal (15.4%) and primary BSI (9.1%). One-hundred-seventy-eight patients (48.9%) received the first antibiotic dose within 3 hours from triage. Multivariate analysis identified evaluation by internal medicine intern, triage scales 1 and 2, as predictors of early antibiotic administration, while, primary BSI was associated with delayed antibiotic administration. Thirty-day mortality was 12.9% (47 patients). Charlson comorbidity index, septic shock, low respiratory tract infection were independently associated with mortality, while antibiotic administration within 3 hours from triage and source control within 48 hours from triage were associated with survival. CONCLUSIONS: The majority of patients received the first antibiotic dose after 3 hours Patients evaluated by surgical interns had a significant delay in administration of antibiotics as compared to those treated by medical interns.