Association between Mitochondrial DNA Sequence Variants and V˙O2 max Trainability.

Purpose: We designed the study to determine whether mitochondrial DNA (mtDNA) haplogroup, sequence, and heteroplasmy differed between individuals previously characterized as low (LR) or high responders (HR) as defined by their maximal oxygen uptake response to a standardized aerobic exercise training program.

Methods: DNA was isolated from whole blood in subjects from the HERITAGE Family Study that were determined to be either HR (n = 15) or LR (n = 15). mtDNA was amplified by long-range polymerase chain reaction, then tagged with Nextera libraries and sequenced on a MiSeq instrument.

Multi-walled carbon nanotubes upregulate mitochondrial gene expression and trigger mitochondrial dysfunction in primary human bronchial epithelial cells.

Nanomaterials are a relatively new class of materials that acquire novel properties based on their reduced size. While these materials have widespread use in consumer products and industrial applications, the potential health risks associated with exposure to them remain to be fully characterized. Carbon nanotubes are among the most widely used nanomaterials and have high potential for human exposure by inhalation.

Inter-individual variation in health and disease associated with pulmonary infectious agents.

Respiratory infectious diseases resulting from bacterial or viral pathogens such as Mycobacterium tuberculosis, Streptococcus pneumoniae, respiratory syncytial virus (RSV), or influenza, are major global public health concerns. Lower respiratory tract infections are leading causes of morbidity and mortality, only behind ischemic heart disease and stroke (GBD 2015 LRI Collaborators in Lancet Infect Dis 17(11):1133-1161, 2017). Developing countries are particularly impacted by these diseases.

Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants.

Background: Respiratory syncytial virus (RSV) is the global leading cause of lower respiratory tract infection in infants. Nearly 30% of all infected infants develop severe disease including bronchiolitis, but susceptibility mechanisms remain unclear.

Methods: We infected a panel of 30 inbred strains of mice with RSV and measured changes in lung disease parameters 1 and 5days post-infection and they were used in genome-wide association (GWA) studies to identify quantitative trait loci (QTL) and susceptibility gene candidates.

Effects of mannose-binding lectin on pulmonary gene expression and innate immune inflammatory response to ozone.

Ozone is a common, potent oxidant pollutant in industrialized nations. Ozone exposure causes airway hyperreactivity, lung hyperpermeability, inflammation, and cell damage in humans and laboratory animals, and exposure to ozone has been associated with exacerbation of asthma, altered lung function, and mortality. The mechanisms of ozone-induced lung injury and differential susceptibility are not fully understood.

Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice.

Background: Ozone is a highly toxic air pollutant and global health concern. Mechanisms of genetic susceptibility to ozone-induced lung inflammation are not completely understood. We hypothesized that Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation.

Genome-wide association mapping of acute lung injury in neonatal inbred mice.

Reactive oxygen species (ROS) contribute to the pathogenesis of many acute and chronic pulmonary disorders, including bronchopulmonary dysplasia (BPD), a respiratory condition that affects preterm infants. However, the mechanisms of susceptibility to oxidant stress in neonatal lungs are not completely understood. We evaluated the role of genetic background in response to oxidant stress in the neonatal lung by exposing mice from 36 inbred strains to hyperoxia (95% O2) for 72 h after birth.

Dual p38/JNK mitogen activated protein kinase inhibitors prevent ozone-induced airway hyperreactivity in guinea pigs.

Ozone exposure causes airway hyperreactivity and increases hospitalizations resulting from pulmonary complications. Ozone reacts with the epithelial lining fluid and airway epithelium to produce reactive oxygen species and lipid peroxidation products, which then activate cell signaling pathways, including the mitogen activated protein kinase (MAPK) pathway. Both p38 and c-Jun NH2 terminal kinase (JNK) are MAPK family members that are activated by cellular stress and inflammation.

Three days after a single exposure to ozone, the mechanism of airway hyperreactivity is dependent on substance P and nerve growth factor.

Ozone causes persistent airway hyperreactivity in humans and animals. One day after ozone exposure, airway hyperreactivity is mediated by release of eosinophil major basic protein that inhibits neuronal M(2) muscarinic receptors, resulting in increased acetylcholine release and increased smooth muscle contraction in guinea pigs. Three days after ozone, IL-1β, not eosinophils, mediates ozone-induced airway hyperreactivity, but the mechanism at this time point is largely unknown.

Neural control of airway inflammation.

Abnormal neural function contributes to the pathogenesis of airway disease. In addition to affecting airway physiology, the nerves produce and release inflammatory mediators, contributing to the recruitment and activation of leukocytes. Activated inflammatory cells in turn affect the function of airway nerves, changing the production and release of neurotransmitters.

IL-1 receptors mediate persistent, but not acute, airway hyperreactivity to ozone in guinea pigs.

Ozone exposure in the lab and environment causes airway hyperreactivity lasting at least 3 days in humans and animals. In guinea pigs 1 day after ozone exposure, airway hyperreactivity is mediated by eosinophils that block neuronal M(2) muscarinic receptor function, thus increasing acetylcholine release from airway parasympathetic nerves. However, mechanisms of ozone-induced airway hyperreactivity change over time, so that depleting eosinophils 3 days after ozone makes airway hyperreactivity worse rather than better.