Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis.

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells.

Associations of Smoking, Cytomegalovirus Serostatus, and Natural Killer Cell Phenotypes in Smokers With and At Risk for COPD.

Introduction: Chronic obstructive disease (COPD) risk factors, smoking, and chronic infection (cytomegalovirus [CMV]) may mold natural killer (NK) cell populations. What is not known is the magnitude of the effect CMV seropositivity imparts on populations of smokers with and at risk for COPD. We investigate the independent influence of CMV seropositivity on NK cell populations and differential effects when stratifying by COPD and degree of smoking history.

Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis.

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored the mechanisms of silica-induced pulmonary fibrosis in a mouse model using multiple modalities including whole-lung single-nucleus RNA sequencing. These analyses revealed that in addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor-κB ligand (RANKL) in pulmonary lymphocytes and alveolar type II cells.

Cytomegalovirus Seropositivity is Associated with Airflow Limitation in a Cohort of Veterans with a High Prevalence of Smoking.

Background: Cytomegalovirus (CMV) represents an understudied chronic infection, usually contracted early in life, that causes chronic immune system alterations which may contribute to airflow limitations in a cohort of veterans with a high prevalence of smoking. We studied 172 participants at-risk for and with airflow limitation with available CMV serology to assess the relationship between CMV infection and chronic obstructive pulmonary disease (COPD)-related outcomes.

Methods: The study cohort includes 172 veterans who are smokers with or at risk for the development of COPD.

Unique natural killer cell subpopulations are associated with exacerbation risk in chronic obstructive pulmonary disease.

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide. COPD is frequently punctuated by acute exacerbations that are precipitated primarily by infections, which increase both morbidity and mortality and inflates healthcare costs. Despite the significance of exacerbations, little understanding of immune function in COPD exacerbations exists.

MAPK mutations and cigarette smoke promote the pathogenesis of pulmonary Langerhans cell histiocytosis.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare smoking-related lung disease characterized by dendritic cell (DC) accumulation, bronchiolocentric nodule formation, and cystic lung remodeling. Approximately 50% of patients with PLCH harbor somatic BRAF-V600E mutations in cells of the myeloid/monocyte lineage. However, the rarity of the disease and lack of animal models have impeded the study of PLCH pathogenesis.

NKG2D Regulation of Lung Pathology and Dendritic Cell Function Following Respiratory Syncytial Virus Infection.

Background: Respiratory syncytial virus (RSV) is a common cause of respiratory tract infection in vulnerable populations. Natural killer (NK) cells and dendritic cells (DC) are important for the effector functions of both cell types following infection.

Methods: Wild-type and NKG2D-deficient mice were infected with RSV.

Tuberin Regulates Prostaglandin Receptor-Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells.

Tuberous sclerosis complex (TSC) is a tumor-suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in or resulting in hyperactivation of mTOR complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain.

Dendritic Cell Trafficking and Function in Rare Lung Diseases.

Dendritic cells (DCs) are highly specialized immune cells that capture antigens and then migrate to lymphoid tissue and present antigen to T cells. This critical function of DCs is well defined, and recent studies further demonstrate that DCs are also key regulators of several innate immune responses. Studies focused on the roles of DCs in the pathogenesis of common lung diseases, such as asthma, infection, and cancer, have traditionally driven our mechanistic understanding of pulmonary DC biology.

NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline.

Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that leads to progressive cyst formation and accelerated loss of pulmonary function. Neoplastic smooth muscle cells from an unknown source metastasize to the lung and drive destructive remodeling. Given the role of NK cells in immune surveillance, we postulated that NK cell activating receptors and their cognate ligands are involved in LAM pathogenesis.

Cutting Edge: CLEC5A Mediates Macrophage Function and Chronic Obstructive Pulmonary Disease Pathologies.

Chronic obstructive pulmonary disease (COPD) is a devastating disease with no effective therapies. We investigated the role of the C-type lectin receptor, CLEC5A, in macrophage activation and pulmonary pathogenesis in a mouse model of COPD. We demonstrate that CLEC5A is expressed on alveolar macrophages in mice exposed long-term to cigarette smoke (CS), as well as in human smokers.

Oral tungstate (Na2WO4) exposure reduces adaptive immune responses in mice after challenge.

Tungstate (WO²⁻₄) has been identified as a ground water contaminant at military firing ranges and can be absorbed by ingestion. In this study, C57BL6 mice were exposed to sodium tungstate (Na2WO4·2H2O) (0, 2, 62.5, 125, and 200 mg/kg/day) in their drinking water for an initial 28-day screen and in a one-generation (one-gen) model.

Mouse embryonic stem cells undergo charontosis, a novel programmed cell death pathway dependent upon cathepsins, p53, and EndoG, in response to etoposide treatment.

Embryonic stem cells (ESCs) are hypersensitive to many DNA damaging agents and can rapidly undergo cell death or cell differentiation following exposure. Treatment of mouse ESCs (mESCs) with etoposide (ETO), a topoisomerase II poison, followed by a recovery period resulted in massive cell death with characteristics of a programmed cell death pathway (PCD). While cell death was both caspase- and necroptosis-independent, it was partially dependent on the activity of lysosomal proteases.

Tissue distribution of tungsten in mice following oral exposure to sodium tungstate.

Heavy metal tungsten alloys have replaced lead and depleted uranium in many munitions applications, due to public perception of these elements as environmentally unsafe. Tungsten materials left in the environment may become bioaccessible as tungstate, which might lead to population exposure through water and soil contamination. Although tungsten had been considered a relatively inert and toxicologically safe material, recent research findings have raised concerns about possible deleterious health effects after acute and chronic exposure to this metal.

A ribonucleotide reductase inhibitor reverses burn-induced inflammatory defects.

Immature myeloid cells have been implicated as a source of postburn inflammation, and the appearance of these cells correlates with enhanced upregulation of hematopoiesis. The role of proliferative cells in postburn immune changes has not been directly tested. Gemcitabine, a ribonucleotide reductase inhibitor, has been shown to deplete proliferative immature myeloid cells in tumor models while sparing mature cells, leading to restored lymphocyte function and tumor regression.

Sodium tungstate (Na2WO4) exposure increases apoptosis in human peripheral blood lymphocytes.

The potential for adverse health effects of using tungsten and its alloys in military munitions are an important concern to both civilians and the US military. The toxicological implications of exposure to tungsten, its alloys, and the soluble tungstate (Na(2)WO(4)) are currently under investigation. To examine tungstate toxicity, a series of experiments to determine its in vitro effects on cells of the immune system were performed.

Employing a recombinant HLA-DR3 expression system to dissect major histocompatibility complex II-thyroglobulin peptide dynamism: a genetic, biochemical, and reverse immunological perspective.

Previously, we have shown that statistical synergism between amino acid variants in thyroglobulin (Tg) and specific HLA-DR3 pocket sequence signatures conferred a high risk for autoimmune thyroid disease (AITD). Therefore, we hypothesized that this statistical synergism mirrors a biochemical interaction between Tg peptides and HLA-DR3, which is key to the pathoetiology of AITD. To test this hypothesis, we designed a recombinant HLA-DR3 expression system that was used to express HLA-DR molecules harboring either AITD susceptibility or resistance DR pocket sequences.

Live yeast cell derivative induces c-fos expression in THP-1 monocytes.

Live Yeast Cell Derivative is a medicinal extract of Saccharomyces cerevisiae that has demonstrated efficacy in improving the rate and quality of wound healing in mouse and human systems. However, the mechanisms by which LYCD promotes healing are largely uncharacterized. In this report, we demonstrate that LYCD has effects on the transcriptional profile of the human monocytic cell line THP-1.

Thermal injury elevates the inflammatory monocyte subpopulation in multiple compartments.

Recent publications have demonstrated that human resident and inflammatory monocyte (IM) subpopulations have equivalents in rodents. The effect of thermal injury upon these subpopulations has not been studied. Mice were given a scald burn and killed on postburn days (PBDs) 2, 4, and 8.