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Browsing by Subject "ARDS"

Now showing 1 - 4 of 4
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    Characterizing the Effects of Composition on Lung Surfactant Monolayer Collapse through Fluorescence Imaging
    (2024-04) Kelpsas, Josephine, K; McAllister, Zachary; Zasadzinski, Joseph, A
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    A materials science approach to treating respiratory distress syndromes and advanced COVID-19 infections
    (2023-01) Ciutara, Clara
    Lung Surfactant (LS) is a mixture of lipids and proteins lining the air/water interface in the alveoli. LS facilitates breathing, mainly by reducing the air/water interfacial tension, and thus the energy required to breathe. The lack of functional LS is associated with two pathological conditions: Neonatal Respiratory Distress Syndrome (NRDS) and Acute Respiratory Distress Syndrome (ARDS). NRDS occurs in premature infants who have not developed LS secretion system, while ARDS happens when the lung is injured and the inflammatory response leads to LS inactivation. To date, the state-of-art replacement surfactants are extracted from animals, of which the exact composition is not known and could vary from animal to animal. This raises concerns regarding contamination and quality-control. Additionally, the animal-derived LS has not been effective in treating ARDS as the body's innate immune system inactivates LS, both endogenous and exogenous. This lack of quality-controlled, effective LS thus calls for a systematic understanding of clinical lung surfactant formulation, as well as an investigative study into LS inactivation mechanism during ARDS progression and its treatment. The contribution of my PhD work can be divided into three major themes. First, I have developed an understanding of how formulation affects clinical lung surfactant viscoelasticity and subsequent intratracheal delivery to treat neonatal respiratory distress syndrome. Second, I demonstrated that Langmuir trough, a tool classically used to study lipid monolayer, can be used for measurements of dilatational modulus (resistance to area change) of the lung surfactant system and inflammation products. Third, I investigated dynamics of lung surfactant in the presence of inflammation products, and discovered a mechanism by which a potentially fatal lung collapse can take place. Ultimately, the unified understanding of these phenomena will serve as a powerful weapon against the respiratory distress syndromes. This overarching understanding of the LS system can further be extended to other membrane and interfacial phenomena.
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    Protein expression profile of rat type two alveolar epithelial cells during hyperoxic stress and recovery
    (2013-05) Bhargava, Maneesh
    Rationale: In rodent model systems, the sequential changes in lung morphology resulting from hyperoxic injury are well characterized, and are similar to changes in human acute respiratory distress syndrome (ARDS). In the injured lung, alveolar type two (AT2) epithelial cells play a critical role restoring the normal alveolar structure. Thus characterizing the changes in AT2 cells will provide insights into the mechanisms underpinning the recovery from lung injury. Methods: We applied an unbiased systems level proteomics approach to elucidate molecular mechanisms contributing to lung repair in a rat hyperoxic lung injury model. AT2 cells were isolated from rat lungs at predetermined intervals during hyperoxic injury and recovery. Protein expression profiles were determined by using iTRAQ® with tandem mass spectrometry. Results: Of 959 distinct proteins identified, 183 significantly changed in abundance during the injury-recovery cycle. Gene Ontology enrichment analysis identified cell cycle, cell differentiation, cell metabolism, ion homeostasis, programmed cell death, ubiquitination, and cell migration to be significantly enriched by these proteins. Gene Set Enrichment Analysis of data acquired during lung repair revealed differential expression of gene sets that control multicellular organismal development, systems development, organ development, and chemical homeostasis. More detailed analysis identified activity in two regulatory pathways, JNK and miR 374. A Short Time-series Expression Miner (STEM) algorithm identified protein clusters with coherent changes during injury and repair. Conclusion: Coherent changes occur in the AT2 cell proteome in response to hyperoxic stress. These findings offer guidance regarding the specific molecular mechanisms governing repair of the injured lung.
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    Proteomic Studies in Acute Respiratory Failure
    (2015-08) Bhargava, Maneesh
    Respiratory failure is a syndrome of impaired gas exchange resulting in abnormal oxygenation and carbon dioxide elimination. Lung damage seen in Acute Respiratory Distress Syndrome (ARDS) and Idiopathic Pneumonia Syndrome (IPS) cause acute respiratory failure and result in a high mortality and morbidity. Our objective is to gain novel insights into the pathways and biological processes that occur in response to diffuse lung injury by using comprehensive protein expression profiling in combination with bioinformatics tools. We characterized the protein expression in the Bronchoalveolar lavage fluid (BALF) from subjects with ARDS and also in hematopoietic stem cell transplantation (HSCT) recipients. For our studies, ARDS cases were grouped into survivors and non-survivors. The HSCT recipients were assigned to either infectious lung injury or IPS, i.e. non-infectious lung injury. The BALF samples were processed by desalting, concentration and removal of high abundance proteins. Enriched medium and low abundant protein fractions were trypsin digested and labeled with the iTRAQ reagent for mass spectrometry (MS). The complex mixture of iTRAQ labeled peptides was analyzed by 2D capillary LC-MS/MS on an Orbitrap Velos system in HCD mode for data-dependent peptide tandem MS. Protein identification employed a target decoy strategy using ProteinPilot. To determine the biologic relevance of the differentially expressed proteins we used Database for Visualization and Annotation for Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA). In the studies done on pooled BALF described in Chapter 3, we identified 792 proteins at a global FDR of <= 1%. The proteins that were more abundant in early phase survivors represented the GO groups involved in coagulation, fibrinolysis and wound healing, cation homeostasis and activation of the immune response. In contrast, non-survivors had evidence of carbohydrate catabolism, collagen deposition and actin cytoskeleton reorganization. These proof of concept studies identified early differences in the BALF from ARDS survivors compared to non-survivors. As a follow-up, we characterized BALF from the individual subject with ARDS, 20 survivors and 16 non-survivors (Chapter 4). To accomplish this we performed six eight-plex iTRAQ LC-MS/MS experiments, and we identified 1122 unique proteins in the BALF. The proteins that had a differential expression between survivors and non-survivors represented three canonical pathways -- acute phase response signaling, complement system activation, LXR/RXR activation- and four IPA Diseases and Functions- cellular movement, immune cell trafficking, hematological system development and inflammatory response. Similar to our prior studies, GO biological processes annotated to these proteins included programmed cell death, collagen metabolic processes, and acute inflammatory response. The sparse logistic regression model identified twenty proteins that predicted survival in ARDS. For the studies conducted in HSCT recipients (Chapter 5), we performed five eight-plex iTRAQ LC-MS/MS experiments and identified 1125 unique proteins. The proteins that had a differential expression between IPS and infectious lung injury enrich GO biological terms of immune response, leucocyte adhesion, coagulation, wound healing, cell migration, glycolysis, and apoptosis. In summary, the BALF protein expression profile identifies key differences in the biological processes in different subgroups of patients with diffuse lung injury. These differences position us to develop diagnostic and prognostic biomarkers and identify new targets for pharmacological therapy.