Recombinant Human Plasma Gelsolin Stimulates Phagocytosis while Diminishing Excessive Inflammatory Responses in Mice with Pseudomonas aeruginosa Sepsis

Abstract

Plasma gelsolin (pGSN) is a highly conserved abundant circulating protein, characterized by diverse immunomodulatory activities including macrophage activation and the ability to neutralize pro-inflammatory molecules produced by the host and pathogen. Using a murine model of Gram-negative sepsis initiated by the peritoneal instillation of Pseudomonas aeruginosa Xen 5, we observed a decrease in the tissue uptake of IRDye®800CW 2-deoxyglucose, an indicator of inflammation, and a decrease in bacterial growth from ascitic fluid in mice treated with intravenous recombinant human plasma gelsolin (pGSN) compared to the control vehicle. Pretreatment of the murine macrophage line RAW264.7 with pGSN, followed by addition of Pseudomonas aeruginosa Xen 5, resulted in a dose-dependent increase in the proportion of macrophages with internalized bacteria. This increased uptake was less pronounced when cells were pretreated with pGSN and then centrifuged to remove unbound pGSN before addition of bacteria to macrophages. These observations suggest that recombinant plasma gelsolin can modulate the inflammatory response while at the same time augmenting host antibacterial activity.

Recombinant human plasma gelsolin (rhu-pGSN) in a patient hospitalized with critical COVID-19 pneumonia

“…Plasma gelsolin (pGSN) levels fall early after SARS-CoV-2 infection in direct relationship to the severity of the ultimate illness ( Abers et al, 2021 , Messner et al, 2020 , Overmyer et al, 2021 ). Recombinant human (rhu-)pGSN) improves disease outcomes in diverse animal models of infectious and non-infectious inflammation ( Piktel et al, 2010 , Yang et al, 2019 , DiNubile et al, 2020 ). Under a compassionate-use agreement, rhu-pGSN was given intravenously to an intubated patient with critical COVID-19 pneumonia and progressive hypoxemia despite dexamethasone, antibiotics, high-flow nasal O 2 , and ICU care.…”

“…Concurrently, pGSN enhances bacterial uptake and killing by macrophages at the infected site ( Ordija et al, 2017 , Yang et al, 2015 ). Once leaked cytoskeletal actin and nuclear/mitochondrial DNA are cleared, free pGSN can bind proinflammatory lipid and peptide mediators to foster resolution of local injury and prevent spread to distant uninvolved organs ( Piktel et al, 2010 ). Consequently, pGSN boosts the early innate immune response to clear pathogens at the infected site while tempering the injurious consequences of excessively prolonged or distant inflammation.…”

“…In severe or critical COVID-19, circulating pGSN levels drop ( Abers et al, 2021 , Messner et al, 2020 , Overmyer et al, 2021 ). Rhu-pGSN repletion may counteract host-mediated lung damage in animal models ( Piktel et al, 2010 , Yang et al, 2019 , DiNubile et al, 2020 ). Our ultimate goal is to investigate if supplementing depleted levels of pGSN under such circumstances would be beneficial in aborting the pathophysiological events leading to acute respiratory distress syndrome.…”

Formation of an Algorithm for Diagnosing Syndromes of Exercise-Induced Muscle Damage and Delayed Onset of Muscle Soreness in Athletes

“…Благодаря своему участию в иммунологических процессах и взаимодействию с различными клетками иммунной системы, GSN является потенциальным кандидатом для различных терапевтических и диагностических применений в клинике и спорте [39−41]. Не столь давно открытый белок AGP − α 1кислый гликопротеин − один из основных острофазных белков [39], концентрация которых в сыворотке крови может увеличиваться в 3-4 раза при воспалительных процессах разного генеза, на сегодня также является одним из самых точных прогностических факторах при инфламмации [40]. Члены суперсемейства гельсолинов являются Ca (2+)-зависимыми, многодоменными регуляторами цитоскелета актина.…”

Safety and Pharmacokinetics of Recombinant Human Plasma Gelsolin in Patients Hospitalized for Nonsevere Community-Acquired Pneumonia

“…Once leaked cytoskeletal actin and nuclear DNA are cleared, free pGSN can bind proinflammatory lipid and peptide mediators to foster resolution of local inflammatory injury and prevent its spread to distant uninvolved organs (12,(22)(23)(24)27). Consequently, pGSN boosts the early innate immune response to clear pathogens at the infected site while tempering the injurious consequences of excessively prolonged or distant inflammation (26,(28)(29)(30)(31).…”