Upon discovery as endogenously produced gaseous signaling molecule, research into hydrogen sulfide biology has increased dramatically over the past 15 years. Animal, human, and in-vitro studies have shown that the molecule exerts a wide range of physiological as well as pathophysiological actions. For this reason, the gas is being investigated for its therapeutic potential and, despite a prolific rise in publications, H2S research has suffered from inconsistent results in several biological fields. This is most apparent in the field of inflammation where the gas has been shown to exert both pro and anti-inflammatory actions. It is our, as well as others, hypothesis that the cause of these paradoxical results is variation in temporal release profiles of different H2S-releasing donor molecules. Current methods of H2S administration do not allow for temporal concentration control. Donor molecules such as sulfide salts are most commonly used which release a bolus of H2S before dissipating within seconds. Other slow-releasing donors steadily increase their release before plateauing around 24 hours. Large atmospheric chambers using H2S gas cylinders, are used by a select few labs but are only able to provide a single constant concentration, much like incubators. Among the donor molecules, fast-releasing donors have been shown to be both pro-inflammatory and anti-inflammatory while slow-releasing donors appear to attenuate the inflammatory response. These opposite results show the importance of controlling temporal exposure profiles in hydrogen sulfide research. We will introduce a microfluidic multiwell insert device to precisely deliver various H2S concentrations in the time. As oxygen tension has also been shown to influence H2S lifetime, we will also introduce oxygen control to investigate paradoxical effects seen under different oxygen concentrations. Using human umbilical venous endothelial cells (HUVECS) and human U937 monocytes, we will use the device to investigate the threshold concentrations and durations that govern the transition from pro to anti-inflammatory phenotypes. Overall, this study will introduce a much-needed gas delivery platform for precise temporal control of H2S and oxygen and use it to study the role of H2S in inflammation. It is our hope that this device will standardize in-vitro H2S exposure experiments as well as other environmental gases in the future.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|