Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging.

Reactivation and dysregulation of the mTOR signaling pathway are a hallmark of aging and chronic lung disease; however, the impact on microvascular progenitor cells (MVPCs), capillary angiostasis, and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue-resident MVPCs present in both adult mouse and human lungs using functional, lineage, and transcriptomic analyses. These studies link human and mouse MVPC-specific mTORC1 activation to decreased stemness, angiogenic potential, and disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function.

Alpha-1 antitrypsin inhibits fractalkine-mediated monocyte-lung endothelial cell interactions.

Chronic obstructive pulmonary disease (COPD) is characterized by nonresolving inflammation fueled by breach in the endothelial barrier and leukocyte recruitment into the airspaces. Among the ligand-receptor axes that control leukocyte recruitment, the full-length fractalkine ligand (CX3CL1)-receptor (CX3CR1) ensures homeostatic endothelial-leukocyte interactions. Cigarette smoke (CS) exposure and respiratory pathogens increase expression of endothelial sheddases, such as a-disintegrin-and-metalloproteinase-domain 17 (ADAM17, TACE), inhibited by the anti-protease α-1 antitrypsin (AAT).

Colocalization of Gene Expression and DNA Methylation with Genetic Risk Variants Supports Functional Roles of and in Idiopathic Pulmonary Fibrosis.

Common genetic variants have been associated with idiopathic pulmonary fibrosis (IPF). To determine functional relevance of the 10 IPF-associated common genetic variants we previously identified. We performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals and functional validation by luciferase reporter assays.

Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator-activated receptor γ.

Resolution of inflammation is an active process that is tightly regulated to achieve repair and tissue homeostasis. In the absence of resolution, persistent inflammation underlies the pathogenesis of chronic lung disease such as chronic obstructive pulmonary disease (COPD) with recurrent exacerbations. Over the course of inflammation, macrophage programming transitions from pro-inflammatory to pro-resolving, which is in part regulated by the nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ).

Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency.

Deficiency of ASM (acid sphingomyelinase) causes the lysosomal storage Niemann-Pick disease (NPD). Patients with NPD type B may develop progressive interstitial lung disease with frequent respiratory infections. Although several investigations using the ASM-deficient (ASMKO) mouse NPD model revealed inflammation and foamy macrophages, there is little insight into the pathogenesis of NPD-associated lung disease.

The MUC5B-associated variant rs35705950 resides within an enhancer subject to lineage- and disease-dependent epigenetic remodeling.

The G/T transversion rs35705950, located approximately 3 kb upstream of the MUC5B start site, is the cardinal risk factor for idiopathic pulmonary fibrosis (IPF). Here, we investigate the function and chromatin structure of this -3 kb region and provide evidence that it functions as a classically defined enhancer subject to epigenetic programming. We use nascent transcript analysis to show that RNA polymerase II loads within 10 bp of the G/T transversion site, definitively establishing enhancer function for the region.

Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression.

The glucocorticoid receptor (NR3C1, also known as GR) binds to specific DNA sequences and directly induces transcription of anti-inflammatory genes that contribute to cytokine repression, frequently in cooperation with NF-kB. Whether inflammatory repression also occurs through local interactions between GR and inflammatory gene regulatory elements has been controversial. Here, using global run-on sequencing (GRO-seq) in human airway epithelial cells, we show that glucocorticoid signaling represses transcription within 10 min.

Mice Lacking Fatty Acid-Binding Protein 5 Are Resistant to Listeria monocytogenes.

To investigate the role of fatty acid-binding protein 5 (FABP5) in infectious diseases, FABP5-deficient mice were challenged with Listeria monocytogenes, a facultative intracellular bacterial pathogen. Interestingly, FABP5-deficient animals were able to clear the infection within 3 days whereas control wild-type (WT) animals showed comparatively higher bacterial burdens in the liver and spleen. Sections of infected tissues showed an increase in inflammatory foci in WT mice compared to FABP5-deficient mice.

Impact of fatty acid binding protein 5-deficiency on COPD exacerbations and cigarette smoke-induced inflammatory response to bacterial infection.

Background: Although cigarette smoking (CS) is by far the most important risk factor of chronic obstructive pulmonary disease (COPD), repeated and sustained infections are clearly linked to disease pathogenesis and are responsible for acute inflammatory flares (i.e. COPD exacerbations).

The ion channel, TRPM2, contributes to the pathogenesis of radiodermatitis.

Radiodermatitis is a painful side effect for cancer patients undergoing radiotherapy. Irradiation of the skin causes inflammation and breakdown of the epidermis and can lead to significant morbidity and mortality in severe cases, as seen in exposure from accidents or weapons such as "dirty bombs" and ultimately leads to tissue fibrosis. However, the pathogenesis of radiodermatitis is not fully understood.

Rapid clearance of heavy chain-modified hyaluronan during resolving acute lung injury.

Background: Several inflammatory lung diseases display abundant presence of hyaluronic acid (HA) bound to heavy chains (HC) of serum protein inter-alpha-inhibitor (IαI) in the extracellular matrix. The HC-HA modification is critical to neutrophil sequestration in liver sinusoids and to survival during experimental lipopolysaccharide (LPS)-induced sepsis. Therefore, the covalent HC-HA binding, which is exclusively mediated by tumor necrosis factor α (TNFα)-stimulated-gene-6 (TSG-6), may play an important role in the onset or the resolution of lung inflammation in acute lung injury (ALI) induced by respiratory infection.

The TRPM2 ion channel contributes to cytokine hyperproduction in a mouse model of Down Syndrome.

Trisomy 21 (Down Syndrome, DS) is the most common chromosomal anomaly. Although DS is mostly perceived as affecting cognitive abilities and cardiac health, individuals with DS also exhibit dysregulated immune functions. Levels of pro-inflammatory cytokines are increased, but intrinsic alterations of innate immunity are understudied in DS.

Cigarette smoke inhibits LPS-induced FABP5 expression by preventing c-Jun binding to the FABP5 promoter.

Cigarette smoking is the primary cause of chronic obstructive pulmonary disease (COPD) with repeated and sustained infections linked to disease pathogenesis and exacerbations. The airway epithelium constitutes the first line of host defense against infection and is known to be impaired in COPD. We have previously identified Fatty Acid Binding Protein 5 (FABP5) as an important anti-inflammatory player during respiratory infections and showed that overexpression of FABP5 in primary airway epithelial cells protects against bacterial infection and inflammation.

The beneficial effects of exercise on cartilage are lost in mice with reduced levels of ECSOD in tissues.

Osteoarthritis (OA) is associated with increased mechanical damage to joint cartilage. We have previously found that extracellular superoxide dismutase (ECSOD) is decreased in OA joint fluid and cartilage, suggesting oxidant damage may play a role in OA. We explored the effect of forced running as a surrogate for mechanical damage in a transgenic mouse with reduced ECSOD tissue binding.

A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution.

Background: The enzyme extracellular superoxide dismutase (EC-SOD; SOD3) is a major antioxidant defense in lung and vasculature. A nonsynonomous single-nucleotide polymorphism in EC-SOD (rs1799895) leads to an arginine to glycine amino acid substitution at position 213 (R213G) in the heparin-binding domain. In recent human genetic association studies, this single-nucleotide polymorphism attenuates the risk of lung disease, yet paradoxically increases the risk of cardiovascular disease.

FABP5 deficiency enhances susceptibility to H1N1 influenza A virus-induced lung inflammation.

The early inflammatory response to influenza A virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which inflammatory cells invade the respiratory tract remain unclear. Uncontrolled inflammation and oxidative stress cause lung damage in response to influenza A infection.

Cigarette smoke decreases airway epithelial FABP5 expression and promotes Pseudomonas aeruginosa infection.

Cigarette smoking is the primary cause of Chronic Obstructive Pulmonary Disease (COPD), which is characterized by chronic inflammation of the airways and destruction of lung parenchyma. Repeated and sustained bacterial infections are clearly linked to disease pathogenesis (e.g.

Airway epithelial NF-κB activation promotes Mycoplasma pneumoniae clearance in mice.

Background/objective: Respiratory infections including atypical bacteria Mycoplasma pneumoniae (Mp) contribute to the pathobiology of asthma and chronic obstructive pulmonary disease (COPD). Mp infection mainly targets airway epithelium and activates various signaling pathways such as nuclear factor κB (NF-κB). We have shown that short palate, lung, and nasal epithelium clone 1 (SPLUNC1) serves as a novel host defense protein and is up-regulated upon Mp infection through NF-κB activation in cultured human and mouse primary airway epithelial cells.

The metalloporphyrin antioxidant, MnTE-2-PyP, inhibits Th2 cell immune responses in an asthma model.

MnTE-2-PyP, a superoxide dismutase mimetic, inhibited OVA-induced airway inflammation in mice suggesting an effect on Th2 responsiveness. Thus, we hypothesized that MnTE-2-PyP may alter dendritic cell-Th2 interactions. Bone marrow derived dendritic cells (DC) and OVA(323-339)-specific Th2 cells were cultured separately in the presence or absence of MnTE-2-PyP for 3 days prior to the co-culturing of the two cell types in the presence of an OVA(323-339) peptide and in some cases stimulated with CD3/CD28.

Heat shock factor 1 protects against lung mycoplasma pneumoniae infection in mice.

Heat shock factor 1 (HSF1) is a transcriptional factor that controls the induction of heat shock proteins (e.g. HSP70) in response to stress.

SPLUNC1 promotes lung innate defense against Mycoplasma pneumoniae infection in mice.

Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is highly expressed in normal airways, but is dramatically decreased in allergic and cigarette smoke exposure settings. We have previously demonstrated SPLUNC1 in vitro antibacterial property against Mycoplasma pneumoniae (Mp). However, its in vivo biological functions remain unclear.

SPLUNC1 regulation in airway epithelial cells: role of Toll-like receptor 2 signaling.

Background: Respiratory infections including Mycoplasma pneumoniae (Mp) contribute to various chronic lung diseases. We have shown that mouse short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein was able to inhibit Mp growth. Further, airway epithelial cells increased SPLUNC1 expression upon Mp infection.

Impact of cigarette smoke exposure on innate immunity: a Caenorhabditis elegans model.

Background: Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD) and lung cancer. Respiratory bacterial infections have been shown to be involved in the development of COPD along with impaired airway innate immunity.

Methodology/principal Findings: To address the in vivo impact of cigarette smoke (CS) exclusively on host innate defense mechanisms, we took advantage of Caenorhabditis elegans (C.

CD38 plays a dual role in allergen-induced airway hyperresponsiveness.

The multifunctional surface protein CD38 acts as a receptor with ecto-enzymatic activity, hydrolyzing NAD to generate several products known to exhibit Ca2+-mobilizing properties. Although CD38 is a convenient marker of immune cell development, and an indicator of progression for several diseases, it is not restricted to the immune compartment. To determine the potentially multilayered involvement of CD38 in allergen-induced airway inflammation and hyperreactivity, we dissected the potential role of CD38 as a regulator of immunity, but also pulmonary function.