A protective role for B-1 cells and oxidation-specific epitope IgM in lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a morbid fibrotic lung disease with limited treatment options. The pathophysiology of IPF remains poorly understood, and elucidation of the cellular and molecular mechanisms of IPF pathogenesis is key to the development of new therapeutics. B-1 cells are an innate B cell population which play an important role linking innate and adaptive immunity. B-1 cells spontaneously secrete natural IgM and prevent inflammation in several disease states. One class of these IgM recognize oxidation-specific epitopes (OSE), which have been shown to be generated in lung injury and to promote fibrosis. A main B-1 cell reservoir is the pleural space, adjacent to the typical distribution of fibrosis in IPF. In this study, we demonstrate that B-1 cells are recruited to the lung during injury where they secrete IgM to OSE (IgM OSE ). We also show that the pleural B-1 cell reservoir responds to lung injury through regulation of the chemokine receptor CXCR4. Mechanistically we show that the transcription factor Id3 is a novel negative regulator of CXCR4 expression. Using mice with B-cell specific Id3 deficiency, a model of increased B-1b cells, we demonstrate decreased bleomycin-induced fibrosis compared to littermate controls. Furthermore, we show that mice deficient in secretory IgM ( sIgM -/- ) have higher mortality in response to bleomycin-induced lung injury, which is partially mitigated through airway delivery of the IgM OSE E06. Additionally, we provide insight into potential mechanisms of IgM in attenuation of fibrosis through RNA sequencing and pathway analysis, highlighting complement activation and extracellular matrix deposition as key differentially regulated pathways.

Oxidative Stress in Pulmonary Fibrosis.

Oxidative stress has been linked to various disease states as well as physiological aging. The lungs are uniquely exposed to a highly oxidizing environment and have evolved several mechanisms to attenuate oxidative stress. Idiopathic pulmonary fibrosis (IPF) is a progressive age-related disorder that leads to architectural remodeling, impaired gas exchange, respiratory failure, and death. In this article, we discuss cellular sources of oxidant production, and antioxidant defenses, both enzymatic and nonenzymatic. We outline the current understanding of the pathogenesis of IPF and how oxidative stress contributes to fibrosis. Further, we link oxidative stress to the biology of aging that involves DNA damage responses, loss of proteostasis, and mitochondrial dysfunction. We discuss the recent findings on the role of reactive oxygen species (ROS) in specific fibrotic processes such as macrophage polarization and immunosenescence, alveolar epithelial cell apoptosis and senescence, myofibroblast differentiation and senescence, and alterations in the acellular extracellular matrix. Finally, we provide an overview of the current preclinical studies and clinical trials targeting oxidative stress in fibrosis and potential new strategies for future therapeutic interventions. © 2020 American Physiological Society. Compr Physiol 10:509-547, 2020.

Developmental pathways in the pathogenesis of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and terminal lung disease with no known cure. IPF is a disease of aging, with median age of diagnosis over 65 years. Median survival is between 3 and 5 years after diagnosis. IPF is characterized primarily by excessive deposition of extracellular matrix (ECM) proteins by activated lung fibroblasts and myofibroblasts, resulting in reduced gas exchange and impaired pulmonary function. Growing evidence supports the concept of a pro-fibrotic environment orchestrated by underlying factors such as genetic predisposition, chronic injury and aging, oxidative stress, and impaired regenerative responses may account for disease development and persistence. Currently, two FDA approved drugs have limited efficacy in the treatment of IPF. Many of the genes and gene networks associated with lung development are induced or activated in IPF. In this review, we analyze current knowledge in the field, gained from both basic and clinical research, to provide new insights into the disease process, and potential approaches to treatment of pulmonary fibrosis.

Fibronectin on the Surface of Extracellular Vesicles Mediates Fibroblast Invasion.

Extracellular vesicles (EVs) are endosome and plasma membrane-derived nano-sized vesicles that participate in intercellular signaling. Although EV cargo may signal via multiple mechanisms, how signaling components on the surface of EVs mediate cellular signaling is less well understood. In this study, we show that fibroblast-derived EVs carry fibronectin on the vesicular surface, as evidenced by mass spectrometry-based proteomics (Sequential Window Acquisition of all Theoretical Mass Spectra) and flow-cytometric analyses. Fibroblasts undergoing replicative senescence or transforming growth factor ß1-induced senescence and fibroblasts isolated from human subjects with an age-related lung disorder, idiopathic pulmonary fibrosis, secreted higher numbers of EVs than their respective controls. Fibroblast-derived EVs induced an invasive phenotype in recipient fibroblasts. This invasive fibroblast phenotype was dependent on EV surface localization of fibronectin, interaction with the fibronectin receptor α5ß1 integrin, and activation of invasion-associated signaling pathways involving focal adhesion kinase and Src family kinases. EVs in the cellular supernatant, unbound to the extracellular matrix, were capable of mediating invasion signaling on recipient fibroblasts, supporting a direct interaction of EV surface fibronectin with the plasma membrane of recipient cells. Together, these studies uncover a novel mechanism of EV signaling of fibroblast invasion that may be relevant in the pathogenesis of fibrotic diseases and cancer.

Recurrent chylothorax: a clinical mystery.

Chylothorax is an unusual cause of pleural effusion, typically caused by trauma or malignancy. Waldenstrom's macroglobulinaemia (WM) is a clinicopathological entity demonstrating lymphoplasmacytic lymphoma in the bone marrow with an IgM monoclonal gammopathy in the blood. Recurrent chylous effusions are often resistant to conservative treatment and may require surgical intervention. We present a unique case of a 50-year-old woman with recurrent chylothorax secondary to WM that completely resolved with ibrutinib therapy. To our knowledge, this is the eighth such case reported in literature and the first case of successful resolution of chylothorax with monoclonal antibody therapy.

Right heart thrombus in transit: a series of two cases.

Right heart thrombus in transit is an increasingly recognized medical emergency with very high mortality rate. Echocardiography helps to establish the diagnosis and can differentiate between right heart thrombi that result from atrial fibrillation and those originating from deep venous thrombosis. We present two cases of right heart thrombus in transit diagnosed with echocardiography that were managed with different approaches.