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The alveolar region of the lung is composed of two major epithelial cell types; cuboidal Type 2 cells (AT2s), that produce surfactant proteins, and large, thin, Type1 cells (AT1s), specialized for efficient gas exchange. AT1s cover more than 95% of the alveolar surface and so constitute a major barrier to the entry of pathogenic agents. Relatively few genetic tools are available for studying the development of AT1s, the function of gene expressed in them, and the effect of specifically killing them in vivo ...
Phosphatase activity of the major serine threonine phosphatase, protein phosphatase 2A (PP2A), is blunted in the airways of chronic obstructive pulmonary disease (COPD) subjects, which results in heightened inflammation and proteolytic responses. The objective of this study was to investigate how PP2A activity is modulated in COPD airways. PP2A activity and endogenous inhibitors of PP2A were investigated in animal and cell models of COPD. In primary human bronchial epithelial (HBE) cells isolated from smoke...
The response to allergens by airway epithelial cells help initiate and propagate allergic inflammation in asthma. Caspase recruitment domain-containing membrane-associated guanylate kinase protein 3 (CARMA3), is a scaffold protein that mediates G protein-coupled receptor induced NF-κB activation in airway epithelium. In this study, we demonstrate that mice with CARMA3-deficient airway epithelial cells have reduced airway inflammation, as well as reduced type 2 cytokine production in response to Alternaria ...
[Rationale] Studies showed that TRIM72 is essential for repair of alveolar cell membrane disruptions, and exogenous TRIM72 protein (rhT72) demonstrated tissue-mending properties in animal models of tissue injury. [Objectives] To examine the mechanisms of rhT72-mediated lung cell protection in vitro and to test the efficacy of inhaled rhT72 in reducing tissue pathology in a mouse model of ventilator-induced lung injury (VILI). [Methods] In vitro lung cell injury was induced by glass beads and stretching. VIL...
Early recognition of neoantigen-expressing cells is complex, involving multiple immune cell types. In this study, in vivo, we examined how antigen-presenting cell (APC) subtypes coordinate and induce an immunological response against neoantigen-expressing cells, particularly in the absence of a pathogen-associated molecular pattern (PAMP), which is normally required to license APCs to present foreign or self-antigens as immunogens. Using two reductionist models of neoantigen-expressing cells and two cancer ...
Genome-wide association studies (GWAS) have identified common variants associated with chronic obstructive pulmonary disease (COPD). Whole-genome sequencing (WGS) offers comprehensive coverage of the entire genome compared with genotyping arrays or exome sequencing.
Smoking is a major risk factor driving the tuberculosis (TB) epidemic and smokers' alveolar macrophages (AM) demonstrate significant immune defects following infection. Recently, macrophage glycolytic reprogramming has emerged as crucial in the early host immune response to Mycobacterium tuberculosis (Mtb) infection.
RGS2 is a key modulator of stress in human airway epithelial cells, especially of hyperresponsiveness and mucin hypersecretion, both features of cystic fibrosis (CF). Because its expression can be modulated through the DNA methylation pathway, we hypothesize that RGS2 is downregulated by DNA hypermethylation in CF airway epithelial cells. This downregulation would then lead to an enhanced inflammatory response.
IL-8 dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases including COPD, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible pathologic, changes associated with elevated levels of IL-8 in the lung.
Mechanical ventilation with O-rich gas (MV-O) inhibits alveologenesis and lung growth. We showed that MV-O increases elastase activity and apoptosis in lungs of newborn mice; elastase inhibition by elafin suppressed apoptosis and enabled lung growth. In pilot studies, MV-O reduced lung expression of pro-survival factors, pEGFR and Klf4.
Little is known about whether maternal immune status during pregnancy influences asthma development in the child. We measured cytokine production in supernatants from mitogen-stimulated peripheral blood immune cells collected during and after pregnancy from the mothers of children enrolled in the Tucson Infant Immune Study, a non-selected birth cohort. Physician-diagnosed active asthma in children through age 9 and a history of asthma in their mothers were assessed through questionnaires. Maternal productio...
Vitamin A deficiency strongly predicts the risk of developing tuberculosis (TB) in individuals exposed to Mycobacterium tuberculosis (Mtb). The burden of antibiotic resistant TB is increasing globally therefore there is an urgent need to develop host-directed adjunctive therapies to treat TB. Alveolar macrophages (AM), the niche cell for Mtb, metabolize vitamin A to all-trans retinoic acid (atRA), which influences host immune responses. We sought to determine the mechanistic effects of atRA on the host immu...
Mechanical ventilation (MV) is a life-saving measure for those incapable of adequately ventilating or oxygenating without assistance. Unfortunately, even brief periods of MV result in diaphragm weakness (i.e., "ventilator-induced diaphragm dysfunction" - VIDD) that may render it difficult to wean the ventilator. Prolonged MV is associated with cascading complications and is a strong risk factor for death. Thus, prevention of VIDD may have a dramatic impact on mortality rates. Here, we summarized the current...
Pulmonary vascular remodeling is an angiogenic-related process involving changes in smooth muscle cell (SMC) homeostasis, which is frequently observed in chronic obstructive pulmonary disease (COPD). MicroRNAs (miRNAs) are small non-coding RNAs that regulate mRNA expression levels of many genes leading to the manifestation of cell identity and specific cellular phenotypes. Here we evaluate the miRNA expression profiles of pulmonary arteries (PA) of patients with COPD and its relationship with the regulation...