THE IMPACT OF ACROLEIN ON LUNG FUNCTION: EXPLORATION OF NITROSATIVE STRESS-INDUCED LUNG INJURY AND THERAPEUTIC APPROACHES

Acrolein is an environmental and occupational toxicant known to cause adverse health effects to humans in areas such as the respiratory system, ocular system, and the skin. The NIH’s Chemical Counter-Measures Research Program has taken an interest in acrolein as a toxicant because of the lack of established treatments available for inhaled exposures, only respiratory supportive care. Our work focused on the characterization of the 4mg/kg dose (LD50) acrolein-induced respiratory toxicity by employing mechanical pulmonary testing via the Flexivent to conduct Forced Oscillation Techniques (FOT) with methacholine nebulization to understand the dynamic airway responsiveness as well as Negative Pressure Forced Expiration (NPFE) to determine the static airway properties to determine lung compliance. In addition to using mechanical measurements of lung function, we used a few well-established assays to characterize oxidative stress levels via measurement of glutathione peroxidase activity, nitrosative stress levels by measuring nitrite concentrations, and lipid peroxidation damage by measuring malondialdehyde in bronchoalveolar lavage fluid. The results showed that acrolein-induced respiratory toxicity had considerable effects on airway remodeling measured by mechanical pulmonary testing, with a significant increase in respiratory resistance, a decrease in methacholine response, an increase in lung stiffness and energy dissipation, and an overall decrease in respiratory compliance. The biochemical assays revealed that glutathione peroxidase activity had dropped to less than half in the acrolein group, with significant increases in nitrosative stress and lipid peroxidation markers. Our next set of experiments focused on identifying potential therapeutics for acrolein-induced lipid peroxidation leading to airway remodeling. Mercaptoethylguanidine was of interest because not only is it a selective inhibitor of inducible nitric oxide synthase but also has properties that allow it to scavenge peroxynitrite, mitigating lipid peroxidation formation at different points of the inflammatory pathway. Mercaptoethylguanidine was given via intraperitoneal injection (10mg/kg) at T=0h and T=24h post acrolein exposure. Similar to the previous study, at 48hrs, the mechanical and biochemical properties were assessed. The mice given Mercaptoethylguanidine were shown to have an improvement in weight loss, FOT responses, and an improvement in lung compliance seen in NPFE. The biochemical assay results also showed promise in mitigating acrolein-induced lung damage.

Name thesis:degree_name

Pharmacology and Toxicology (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2025

Author dc:creator

• Alfarawati, Obada 1993-

Advisor dc:contributor.advisor

• Ameredes, Bill (btamered@utmb.edu)

Committee members dc:contributor.committeemember

• Lance Hallberg (lmhallbe@utmb.edu)
• Istvan Boldogh (sboldogh@utmb.edu)
• Giulio Taglialatela (gtaglial@utmb.edu)
• Timothy Corcoran (CorcoranTE@upmc.edu)
• Farrah Kheradmand (farrahk@bcm.edu)

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12886

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12886