Lung & Airway Research on Hypertension and SARS-CoV-2

Disease and Infection of the Respiratory Epithelium

Oxygen is a necessity for all the cells in the human body to function. Our lungs and respiratory system bring air, containing oxygen in, transferring it to the bloodstream where it can be delivered to the rest of the body. This vital process affects every aspect of our body and health. The respiratory epithelium lining most of the respiratory tract plays a critical role in this process, acting as a conduit for air exchange at the lung alveoli. It also serves to moisten and protect the airways against pathogens and inhaled particulates through the action of secretory and ciliated cells and activation of other host immune defenses. Unsurprisingly, disruption in the normal activities of our respiratory epithelium as a result of disease (i.e. pulmonary hypertension) or viral infection (i.e. SARS-CoV-2) can have deleterious effects.

Lifeline® offers a number of human lung and airway cells that have been used by researchers to investigate these conditions and more. Several recent publications featuring Lifeline’s Human Bronchial Tracheal Epithelial (HBTE’s) cells and Small Airway Epithelial Cells (SAEC’s) are highlighted here.

Lifeline HBTE’s and Pulmonary Hypertension Research

Recently, Kuch and Colleagues used Lifeline’s Human Bronchial Tracheal Epithelial (HBTE’s) cells expanded in BronchiaLife™ Complete Medium to investigate concerns regarding the safe delivery and local effects within the airways (i.e. inflammation and ciliary dysfunction) of a popular pulmonary vasodilator, epoprostenol. Intravenous forms of epoprostenol, typically diluted in glycine or sucrose/l-arginine buffers (EPO-GYL and EPO-ARG, respectively) are aerosolized to treat pulmonary hypertension but the safety data for this drug is limited, and previous studies have noted unwanted side effects, which prompted further investigation.

The authors used Bronchialife-expanded HBTE cells differentiated into mucociliary cells on Transwell inserts, which mimics an air-liquid interface. The cells were exposed to EPO-GYL, EPO-ARG, and GLY or ARG diluent controls and assessed for their effect on ciliary beat frequency and cell viability. The data showed impaired ciliary motion and increased cell death in all conditions tested with no observable difference between EPO-GLY and GLY or EPO-ARG and ARG, implying that the side effects of the aerosolized treatment are a result of the highly alkaline pH of ARG and GLY diluents rather than the epoprostenol itself. While the authors recognize this in vitro study has limitations, it is the first one to look directly at the effects of these compounds on airway cells. Additional testing is needed to better understand the clinical effect that high-pH preparations have on airway tissue and associated clinical outcomes, but the use of highly alkaline diluents warrants more consideration.

Lifeline SAEC’s and SARS-CoV-2 (COVID-19) Research

The second publication is by Lee and Colleagues, who used Lifeline’s Small Airway Epithelial Cells (SAEC’s) as a model of the normal human airway epithelium, since it expresses a wide range of cytokine receptors, to understand the genetic programs that cause hyperinflammation in COVID-19 patients. The SAEC’s were stimulated with interferons (IFNs) and subsequently analyzed using RNA-seq to quantify transcriptome changes. Additionally, the dependence of IFN-induced transcriptome response on the JAK/STAT pathway was determined using the JAK inhibitors Baricitinib and Ruxolitinib. Genetic analysis showed that a number of genes associated with the immune response were upregulated as a result of IFN activation. Further ChIP-seq analysis identified key regulatory elements, such as intronic promoters/enhancers, that control these genes. Taken together, the results show that the activation of ACE2, the main receptor for SARS-CoV-2 (COVID-19), as well as a novel short form of ACE2 (dACE2) is controlled by IFN-binding at the 5’ exons of the ACE2 promoter and that IFN activation is regulated upstream by the JAK/STAT pathway.

The importance of research like this publication by Lee and Colleagues that improves our understanding of the complex mechanisms underlying COVID-19 infection cannot be understated. There is much more to learn about the complex regulation of the human ACE2 locus, particularly in the airway epithelium where infectivity is high, but these incremental advances in our knowledge will hopefully help identify better treatments and potentially new therapeutic targets. As of December 10, 2020, SARS-CoV-2 (COVID-19) continues to spread around the world, with over 70.6 million cases and around 1.6 million deaths. At Lifeline, we hope you and your loved ones are staying safe amidst the uncertainty caused by COVID-19.

For more information on Lifeline’s human lung and airway cells as well as the optimized BronchiaLife cell culture media, please click on the links below:

• Small airway cells
• Diseased small airway epithelial cells – asthma and COPD
• Bronchial/tracheal epithelial cells
• Diseased bronchial/tracheal epithelial cells – cystic fibrosis
• Bronchial/tracheal smooth muscle cells
• Lobar bronchial epithelial cells
• Lung fibroblasts
• Lung smooth muscle cells
• Laryngeal epithelial cells
• BronchiaLife Complete Medium Kit

Our blog is updated every other week featuring new research using Lifeline products. If you have used Lifeline products in your research, let us know and your published study could be featured next!