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Papers by Blaze O'Shaughnessy
Communications Biology, 2020
Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet t... more Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide–lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising d-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effectiv...
Shock, 2020
If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.
Airway Pharmacology and Treatment, 2017
American Journal of Respiratory Cell and Molecular Biology, 2019
Platelets are recruited to inflammatory foci and contribute to host defence and inflammatory resp... more Platelets are recruited to inflammatory foci and contribute to host defence and inflammatory responses. Compared to platelet recruitment in haemostasis and thrombosis, the mechanisms of platelet recruitment in inflammation and host defence are poorly understood. Neutrophil recruitment to lung airspaces following inhalation of bacterial LPS requires platelets and PSGL-1 in mice. Given this association between platelets and neutrophils, we investigated whether recruitment of platelets to lungs of mice following LPS inhalation was dependent on PSGL-1, P-selectin, or interaction with neutrophils. BALB/c mice were administered intranasal LPS (O55:B5, 5 mg/kg) and 48 hours later lungs were collected, and platelets and neutrophils were quantified in tissue sections by immunohistochemistry. The effects of functional blocking antibody treatments targeting the platelet-neutrophil adhesion molecules P-selectin, or PSGL-1, or treatment with a neutrophil depleting antibody targeting Ly6G, were tested on the extent of LPS-induced lung platelet recruitment. Separately in Pf4-Cre×mTmG mice, two-photon intravital microscopy was used to image platelet adhesion in live lungs. Inhalation of LPS caused both platelet and neutrophil recruitment to the lung vasculature. However, decreasing lung neutrophil recruitment by blocking PSGL-1, P-selectin, or depleting blood neutrophils had no effect on lung platelet recruitment. Lung intravital imaging revealed increased adhesion of platelets in the lung microvasculature which was not associated with thrombus formation. In conclusion, platelet recruitment to lungs in response to LPS occurs through mechanisms distinct from those mediating neutrophil recruitment, or the occurrence of pulmonary emboli.
American Journal of Respiratory Cell and Molecular Biology, 2018
Platelets have been implicated in pulmonary inflammatory cell recruitment after exposure to aller... more Platelets have been implicated in pulmonary inflammatory cell recruitment after exposure to allergic and nonallergic stimuli, but little is known about the role of platelets in response to pulmonary infection with Pseudomonas aeruginosa. In this study, we have investigated the impact of the experimental depletion of circulating platelets on a range of inflammatory and bacterial parameters, and their subsequent impact on mortality in a murine model of pulmonary infection with P. aeruginosa. P. aeruginosa infection in mice induced a mild, but significant, state of peripheral thrombocytopenia in addition to pulmonary platelet accumulation. Increased platelet activation was detected in infected mice through increased levels of the platelet-derived mediators, platelet factor-4 and b-thromboglobulin, in BAL fluid and blood plasma. In mice depleted of circulating platelets, pulmonary neutrophil recruitment was significantly reduced 24 hours after infection, whereas the incidence of systemic dissemination of bacteria was significantly increased compared with non-platelet-depleted control mice. Furthermore, mortality rates were increased in bacterial-infected mice depleted of circulating platelets. This work demonstrates a role for platelets in the host response toward a gram-negative bacterial respiratory infection.
Pulmonary Pharmacology & Therapeutics, 2017
Lipopolysaccharide (LPS) induced pulmonary neutrophil recruitment and platelet activation is medi... more Lipopolysaccharide (LPS) induced pulmonary neutrophil recruitment and platelet activation is mediated via the P2Y1 and P2Y14 receptors in mice.
Handbook of Experimental Pharmacology, 2016
Asthma and COPD remain two diseases of the respiratory tract with unmet medical needs. This revie... more Asthma and COPD remain two diseases of the respiratory tract with unmet medical needs. This review considers the current state of play with respect to what is known about the underlying pathogenesis of these two chronic inflammatory diseases of the lung. The review highlights why they are different conditions requiring different approaches to treatment and provides a backdrop for the subsequent chapters in this volume discussing recent advances in the pharmacology and treatment of asthma and COPD.
Background. The implication of platelets in inflammatory disorders, such as asthma, has become in... more Background. The implication of platelets in inflammatory disorders, such as asthma, has become increasingly more apparent. Following an inflammatory insult, platelets modulate inflammation by a number of distinct mechanisms, including pulmonary-leukocyte recruitment and release of platelet specific mediators. However, little is known regarding the role of platelets in the regulation of pulmonary infection. Pulmonary colonisation of bacteria, including Pseudomonas aeruginosa (P.aeruginosa) and Staphylococcus aureus (S.aureus) presents a therapeutic challenge due to antimicrobial resistance (AMR). Objectives. In this study, the effect of experimentally induced platelet depletion was investigated on infection and inflammatory parameters in a murine model of pulmonary infection. A new approach in targeting AMR was also tested, using a novel antibiotic enhancer compound, HT61. Methods. C57/B16 mice were experimentally depleted of platelets, 24 hours prior to infection with either sham, P...
Communications Biology, 2020
Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet t... more Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide–lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising d-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effectiv...
Shock, 2020
If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.
Airway Pharmacology and Treatment, 2017
American Journal of Respiratory Cell and Molecular Biology, 2019
Platelets are recruited to inflammatory foci and contribute to host defence and inflammatory resp... more Platelets are recruited to inflammatory foci and contribute to host defence and inflammatory responses. Compared to platelet recruitment in haemostasis and thrombosis, the mechanisms of platelet recruitment in inflammation and host defence are poorly understood. Neutrophil recruitment to lung airspaces following inhalation of bacterial LPS requires platelets and PSGL-1 in mice. Given this association between platelets and neutrophils, we investigated whether recruitment of platelets to lungs of mice following LPS inhalation was dependent on PSGL-1, P-selectin, or interaction with neutrophils. BALB/c mice were administered intranasal LPS (O55:B5, 5 mg/kg) and 48 hours later lungs were collected, and platelets and neutrophils were quantified in tissue sections by immunohistochemistry. The effects of functional blocking antibody treatments targeting the platelet-neutrophil adhesion molecules P-selectin, or PSGL-1, or treatment with a neutrophil depleting antibody targeting Ly6G, were tested on the extent of LPS-induced lung platelet recruitment. Separately in Pf4-Cre×mTmG mice, two-photon intravital microscopy was used to image platelet adhesion in live lungs. Inhalation of LPS caused both platelet and neutrophil recruitment to the lung vasculature. However, decreasing lung neutrophil recruitment by blocking PSGL-1, P-selectin, or depleting blood neutrophils had no effect on lung platelet recruitment. Lung intravital imaging revealed increased adhesion of platelets in the lung microvasculature which was not associated with thrombus formation. In conclusion, platelet recruitment to lungs in response to LPS occurs through mechanisms distinct from those mediating neutrophil recruitment, or the occurrence of pulmonary emboli.
American Journal of Respiratory Cell and Molecular Biology, 2018
Platelets have been implicated in pulmonary inflammatory cell recruitment after exposure to aller... more Platelets have been implicated in pulmonary inflammatory cell recruitment after exposure to allergic and nonallergic stimuli, but little is known about the role of platelets in response to pulmonary infection with Pseudomonas aeruginosa. In this study, we have investigated the impact of the experimental depletion of circulating platelets on a range of inflammatory and bacterial parameters, and their subsequent impact on mortality in a murine model of pulmonary infection with P. aeruginosa. P. aeruginosa infection in mice induced a mild, but significant, state of peripheral thrombocytopenia in addition to pulmonary platelet accumulation. Increased platelet activation was detected in infected mice through increased levels of the platelet-derived mediators, platelet factor-4 and b-thromboglobulin, in BAL fluid and blood plasma. In mice depleted of circulating platelets, pulmonary neutrophil recruitment was significantly reduced 24 hours after infection, whereas the incidence of systemic dissemination of bacteria was significantly increased compared with non-platelet-depleted control mice. Furthermore, mortality rates were increased in bacterial-infected mice depleted of circulating platelets. This work demonstrates a role for platelets in the host response toward a gram-negative bacterial respiratory infection.
Pulmonary Pharmacology & Therapeutics, 2017
Lipopolysaccharide (LPS) induced pulmonary neutrophil recruitment and platelet activation is medi... more Lipopolysaccharide (LPS) induced pulmonary neutrophil recruitment and platelet activation is mediated via the P2Y1 and P2Y14 receptors in mice.
Handbook of Experimental Pharmacology, 2016
Asthma and COPD remain two diseases of the respiratory tract with unmet medical needs. This revie... more Asthma and COPD remain two diseases of the respiratory tract with unmet medical needs. This review considers the current state of play with respect to what is known about the underlying pathogenesis of these two chronic inflammatory diseases of the lung. The review highlights why they are different conditions requiring different approaches to treatment and provides a backdrop for the subsequent chapters in this volume discussing recent advances in the pharmacology and treatment of asthma and COPD.
Background. The implication of platelets in inflammatory disorders, such as asthma, has become in... more Background. The implication of platelets in inflammatory disorders, such as asthma, has become increasingly more apparent. Following an inflammatory insult, platelets modulate inflammation by a number of distinct mechanisms, including pulmonary-leukocyte recruitment and release of platelet specific mediators. However, little is known regarding the role of platelets in the regulation of pulmonary infection. Pulmonary colonisation of bacteria, including Pseudomonas aeruginosa (P.aeruginosa) and Staphylococcus aureus (S.aureus) presents a therapeutic challenge due to antimicrobial resistance (AMR). Objectives. In this study, the effect of experimentally induced platelet depletion was investigated on infection and inflammatory parameters in a murine model of pulmonary infection. A new approach in targeting AMR was also tested, using a novel antibiotic enhancer compound, HT61. Methods. C57/B16 mice were experimentally depleted of platelets, 24 hours prior to infection with either sham, P...