Biology subjects

Albert, C. J.

Publications and source records attributed to Albert, C. J..

4 recordsLinked to original sources

bioRxiv2022

Enhancing Hepatic MBOAT7 Expression Does Not Improve Nonalcoholic Steatohepatitis in Mice

Background & AimsGenetic analyses of human NASH have revealed polymorphisms near the membrane bound O-acyl transferase domain containing 7 (MBOAT7) gene associated with worsened liver injury. NAFLD/NASH also appears to decrease MBOAT7 expression or activity independent of these polymorphisms. Thus, we hypothesized that enhancing MBOAT7 function in NASH would improve pathology. Approach & ResultsMale C57BL6/J mice were infected with adeno-associated virus 8 (AAV8) expressing MBOAT7 under control of the hepatocyte-specific thyroid hormone-binding globulin promoter, or control virus expressing green fluorescent protein (GFP). Mice were infected after NASH induction with either choline-deficient high-fat diet or Gubra Amylin NASH diet and compared to low-fat fed control mice. Both NASH diets increased liver weights, liver triglycerides, and plasma alanine and aspartate aminotransferase (ALT and AST) markers of liver injury, which were modestly yet significantly improved by MBOAT7 overexpression. However, NASH liver histology assessed by categorical scoring was not substantially improved by MBOAT7 overexpression. MBOAT7 regulates the formation of phosphatidylinositol (PI) predominantly by arachidonoylation of lysophosphatidylinositol (LPI). Shotgun lipidomics of NASH GFP-control livers suggested decreased MBOAT7 activity in that LPI content was elevated, and both total and arachidonoylated-PI were reduced. Surprisingly, MBOAT7 overexpression did not rescue the content of most arachidonoylated PI species but did normalize or increase the abundance of several oleate and linoleate-containing PI species. Free arachidonic acid was elevated but the MBOAT7 substrate arachidonoyl-CoA was found to be low in all NASH livers compared to low-fat fed mice, likely due to decreased expression of both long-chain acyl-CoA synthetases (ACSL) 1 and 4 in NASH livers compared to controls. ConclusionsThese results suggest MBOAT7 overexpression fails to measurably improve NASH pathology potentially due to insufficient abundance of its arachidonoyl-CoA substrate in fatty livers.

pathology↗

bioRxiv2022

Recapitulation of Human Pathophysiology and Identification of Forensic Biomarkers in a Translational Swine Model of Chlorine Inhalation Injury

RationaleChlorine gas (Cl2) has been repeatedly used as a chemical weapon, first in World War I and most recently in Syria. Life-threatening Cl2 exposures frequently occur in domestic and occupational environments, and in transportation accidents. There is a knowledge gap in large animal models of Cl2-induced acute lung injury (ALI) required to accurately model human etiology and for the development of targeted countermeasures ObjectiveTo develop a translational model of Cl2-induced ALI in swine to study toxico-pathophysiology and identify biomarkers useful for forensic analysis. MethodsSpecific pathogen-free Yorkshire swine (30-40 kg) of either sex were exposed to Cl2 gas ([≤] 240 ppm for 1 h) or filtered air under anesthesia and controlled mechanical ventilation. ResultsExposure to Cl2 resulted in severe hypoxia and hypoxemia, increased airway resistance and peak inspiratory pressure, and decreased dynamic lung compliance. Chlorine exposure resulted in increased total BALF and neutrophil counts, vascular leakage, and edema compared to the control group. The model recapitulated all three key histopathological features of human ALI, such as neutrophilic alveolitis, deposition of hyaline membranes, and formation of microthrombi. Free and lipid-bound 2-chlorofatty acids and chlorotyrosine-modified proteins (3-chloro-L-tyrosine and 3,5-dichloro-L-tyrosine) were detected in plasma and lung after Cl2-exposure. ConclusionsThe translational model developed in this study replicates key features of humans exposed to Cl2 and is suitable to test medical countermeasures. Specific biomarkers of Cl2 exposure have been identified in plasma and lung tissue samples. Take home messageWe developed a swine model of chlorine gas-induced acute lung injury that exhibits several features of human acute respiratory distress syndrome. We validated chlorinated fatty acids and protein adducts in plasma and lung samples as forensic biomarkers.

pharmacology and toxicology↗

bioRxiv2020

Alterations in the human plasma lipidome in response to Tularemia vaccination

Tularemia is a rare but highly contagious and potentially fatal disease caused by bacteria Francisella tularensis where as few as ten inhaled organisms can lead to an infection, making it one of the most infectious microorganisms known and a potential bioweapon. To better understand the response to a live, attenuated tularemia vaccine and the biological pathways altered post-vaccination, healthy adults were vaccinated by scarification and plasma was collected pre- and post-vaccination for longitudinal lipidomics studies. Using tandem mass spectrometry, we identified and quantified individual lipid molecular species within representative lipid classes in plasma to characterize alterations in the plasma lipidome during the vaccine response. Separately, we targeted oxylipins, a subset of lipid mediators involved in inflammatory pathways. We identified 14 differentially abundant lipid species from eight lipid classes. These included 5-Hydroxyeicosatetraenoic acid (5-HETE), an eicosanoid produced following arachidonic acid liberation and epoxygenation, which is indicative of lipoxygenase activity and, subsequently, inflammation. Results suggest that 5-HETE was metabolized to a dihydroxyeicosatrienoic acid (DHET) by Day 7 post-vaccination, shedding light on the kinetics of the 5-HETE-mediated inflammatory response. In addition to 5-HETE and DHET, we observed pronounced changes in 34:1 phosphatidylinositol, anandamide, oleamide, ceramides, 16:1 cholesteryl ester, and several glycerophospholipids, several of these changes in abundance were correlated with serum cytokines and T cell activation. These data provide new insights into alterations in plasma lipidome post tularemia vaccination, potentially identifying key mediators and pathways involved in vaccine response and efficacy.

biochemistry↗

bioRxiv2019

Phosgene Inhalation Causes Hemolysis and Acute Lung Injury

Phosgene (Carbonyl Chloride, COCl2) remains an important chemical intermediate in many industrial processes such as combustion of chlorinated hydrocarbons and synthesis of solvents (degreasers, cleaners). It is a sweet smelling gas, and therefore does not prompt escape by the victim upon exposure. Supplemental oxygen and ventilation are the only available management strategies. This study was aimed to delineate the pathogenesis and identify novel biomarkers of acute lung injury post exposure to COCl2 gas. Adult male and female C57BL/6 mice (20-25 g), exposed to COCl2 gas (10 or 20ppm) for 10 minutes in environmental chambers, had a dose dependent reduction in PaO2 and an increase in PaCO2, 1 day post exposure. However, mortality increased only in mice exposed to 20ppm of COCl2 for 10 minutes. Correspondingly, these mice (20ppm) also had severe acute lung injury as indicated by an increase in lung wet to dry weight ratio, extravasation of plasma proteins and neutrophils into the bronchoalveolar lavage fluid, and an increase in total lung resistance. The increase in acute lung injury parameters in COCl2 (20ppm, 10min) exposed mice correlated with simultaneous increase in oxidation of red blood cells (RBC) membrane, RBC fragility, and plasma levels of cell-free heme. In addition, these mice had decreased plasmalogen (plasmenylethanolamine) and elevated levels of their breakdown product, polyunsaturated lysophosphatidylethanolamine, in the circulation suggesting damage to cellular plasma membranes. This study highlights the importance of free heme in the pathogenesis of COCl2 lung injury and identifies plasma membrane breakdown product as potential biomarkers of COCl2 toxicity.

physiology↗