scholarly journals The serpentine path to a novel mechanism-based inhibitor of acute inflammatory lung injury

2014 ◽  
Vol 116 (12) ◽  
pp. 1521-1530 ◽  
Author(s):  
Aron B. Fisher
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Oxidant Stress ◽  
Lung Surfactant ◽  
Phospholipase A ◽  
Peroxiredoxin 6 ◽  
The Past ◽  
Research Activities ◽  
Novel Target ◽  
Nadph Oxidase Activation

The Comroe lecture on which this review is based described my research path during the past 45 years, beginning with studies of oxidant stress (hyperoxia) and eventuating in the discovery of a synthetic inhibitor of phospholipase A2activity (called MJ33) that prevents acute lung injury in mice exposed to lipopolysaccharide. In between were studies of lung ischemia, lung surfactant metabolism, the protein peroxiredoxin 6 and its phospholipase A2activity, and mechanisms for NADPH oxidase activation. These seemingly unrelated research activities provided the nexus for identification of a novel target and a potentially novel therapeutic agent for prevention or treatment of acute lung injury.

scholarly journals Genetic inactivation of the phospholipase A2 activity of peroxiredoxin 6 in mice protects against LPS-induced acute lung injury

2019 ◽  
Vol 316 (4) ◽  
pp. L656-L668 ◽  
Author(s):  
José Pablo Vázquez-Medina ◽  
Jian-Quin Tao ◽  
Priyal Patel ◽  
Renata Bannitz-Fernandes ◽  
Chandra Dodia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Phospholipase A2 ◽  
Oxidant Stress ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Mutant Mice ◽  
Peroxiredoxin 6 ◽  
Pyrin Domain

Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme that serves important antioxidant roles by scavenging hydroperoxides and reducing peroxidized cell membranes. Prdx6 also plays a key role in cell signaling by activating the NADPH oxidase, type 2 (Nox2) through its acidic Ca2+-independent phospholipase A2 (aiPLA2) activity. Nox2 generation of O2·−, in addition to signaling, can contribute to oxidative stress and inflammation such as during sepsis-induced acute lung injury (ALI). To evaluate a possible role of Prdx6-aiPLA2 activity in the pathophysiology of ALI associated with a systemic insult, wild-type (WT) and Prdx6-D140A mice, which lack aiPLA2 but retain peroxidase activity were administered intraperitoneal LPS. LPS-treated mutant mice had increased survival compared with WT mice while cytokines in lung lavage fluid and lung VCAM-1 expression, nitrotyrosine levels, PMN infiltration, and permeability increased in WT but not in mutant mice. Exposure of mouse pulmonary microvascular endothelial cells in primary culture to LPS promoted phosphorylation of Prdx6 and its translocation to the plasma membrane and increased aiPLA2 activity as well as increased H2O2 generation, nitrotyrosine levels, lipid peroxidation, NF-κB nuclear localization, and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome assembly; these effects were not seen in Nox2 null cells, Prdx6-D140A cells, or WT cells pretreated with MJ33, an inhibitor of aiPLA2 activity. Thus aiPLA2 activity is needed for Nox2-derived oxidant stress associated with LPS exposure. Since inactivation of aiPLA2 reduced mortality and prevented lung inflammation and oxidative stress in this animal model, the aiPLA2 activity of Prdx6 could be a novel target for prevention or treatment of sepsis-induced ALI.

scholarly journals The Nitrated Fatty Acid 10-Nitro-oleate Diminishes Severity of LPS-Induced Acute Lung Injury in Mice

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Aravind T. Reddy ◽  
Sowmya P. Lakshmi ◽  
Raju C. Reddy
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Lung Diseases ◽  
Oxidant Stress ◽  
Pulmonary Delivery ◽  
Lung Edema ◽  
Potential Utility ◽  
Capillary Leakage ◽  
Nitrated Fatty Acid

Acute lung injury (ALI) is an inflammatory condition culminating in respiratory failure. There is currently no effective pharmacological treatment. Nitrated fatty acids (NFAs) have been shown to exert anti-inflammatory effects. We therefore hypothesized that delivery of NFAs directly to the site of inflammation would reduce the severity of ALI. Pulmonary delivery of 10-nitro-oleate following endotoxin-induced ALI in mice reduced markers of lung inflammation and injury, including capillary leakage, lung edema, infiltration of neutrophils into the lung, and oxidant stress, as well as plasma levels of proinflammatory cytokines. Nitro-oleate delivery likewise downregulated expression of proinflammatory genes by alveolar macrophages, key cells in regulation of lung inflammation. These effects may be accounted for by the observed increases in the activity of PPAR-γand the PPAR-γ-induced antioxidant transcription factor Nrf2, together with the decreased activity of NF-κB. Our results demonstrate that pulmonary delivery of NFAs reduces severity of acute lung injury and suggest potential utility of these molecules in other inflammatory lung diseases.

Peroxiredoxin 6 knockout aggravates cecal ligation and puncture-induced acute lung injury

2019 ◽  
Vol 68 ◽  
pp. 252-258 ◽  
Author(s):  
Xiaocen Wang ◽  
Xiaojing An ◽  
Xun Wang ◽  
Xianglin Hu ◽  
Jing Bi ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cecal Ligation ◽  
Cecal Ligation And Puncture ◽  
Peroxiredoxin 6

scholarly journals Peripheral Leukocytapheresis Attenuates Acute Lung Injury Induced by LipopolysaccharideIn Vivo

2012 ◽  
Vol 2012 ◽  
pp. 1-9
Author(s):  
Zhi-Gao He ◽  
Jian Huang ◽  
Shun-Gang Zhou ◽  
Jing He ◽  
Fang-Xiang Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Distress Syndrome ◽  
Serum Levels ◽  
Partial Removal ◽  
Arterial Blood Gas ◽  
The Past ◽  
Arterial Blood ◽  
Lung Injuries ◽  
Elastase Level

The mortality of acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains high and efforts for prevention and treatments have shown little improvement over the past decades. The present study investigated the efficacy and mechanism of leukocytapheresis (LCAP) to partially eliminate peripheral neutrophils and attenuate lipopolysaccharide (LPS)-induced lung injury in dogs. A total of 24 healthy male mongrel dogs were enrolled and randomly divided into LPS, LCAP and LCAP-sham groups. All animals were injected with LPS to induce endotoxemia. The serum levels of leucocytes, neutrophil elastase, arterial blood gas, nuclear factor-kappa B (NF-κB) subunit p65 in lung tissues were measured. The histopathology and parenchyma apoptosis of lung tissues were examined. We found that 7, 3, and 7 animals in the LPS, LCAP, and sham-LCAP groups, respectively, developed ALI 36 h after LPS infusion. The levels of NF-κB p65 in lung tissue, neutrophils and elastase in blood, decreased significantly following LCAP. LCAP also alleviated apoptosis, and NF-κB p65 in lung tissues. Collectively, our results show that partial removal of leucocytes from peripheral blood decreases elastase level in serum. This, in turn, attenuates lung injuries and may potentially decrease the incidence of ALI.

Genetic Inactivation of the Phospholipase A 2 Activity of Prdx6 Ameliorates Sepsis-induced Acute Lung Injury

2017 ◽  
Vol 112 ◽  
pp. 208-209
Author(s):  
Jose Pablo Vazquez-Medina ◽  
Jian-Quin Tao ◽  
Priyal Patel ◽  
Renata Bannitz-Fernandes ◽  
Chandra Dodia ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Phospholipase A ◽  
Genetic Inactivation ◽  
Phospholipase A 2

scholarly journals Global Trends in Research of Macrophages Associated With Acute Lung Injury Over Past 10 Years: A Bibliometric Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Sheng Wang ◽  
Huanping Zhou ◽  
Li Zheng ◽  
Wanli Zhu ◽  
Lina Zhu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Bibliometric Analysis ◽  
Scientific Output ◽  
Annual Number ◽  
Global Trends ◽  
Citation Score ◽  
The Past ◽  
The Usa

Acute lung injury (ALI) is an intractable disorder associated with macrophages. This bibliometric analysis was applied to identify the characteristics of global scientific output, the hotspots, and frontiers about macrophages in ALI over the past 10 years. We retrieved publications published from 2011 to 2020 and their recorded information from Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC). Bibliometrix package was used to analyze bibliometric indicators, and the VOSviewer was used to visualize the trend and hotspots of researches on macrophages in ALI. Altogether, 2,632 original articles were reviewed, and the results showed that the annual number of publications (Np) concerning the role of macrophages in ALI kept increasing over the past 10 years. China produced the most papers, the number of citations (Nc) and H-index of the USA ranked first. Shanghai Jiaotong University and INT IMMUNOPHARMACOL were the most prolific affiliation and journal, respectively. Papers published by Matute-Bello G in 2011 had the highest local citation score (LCS). Recently, the keywords “NLRP3” and “extracellular vesicles” appeared most frequently. Besides, researches on COVID-19–induced ALI related to macrophages seemed to be the hotspot recently. This bibliometric study revealed that publications related to macrophages in ALI tend to increase continuously. China was a big producer and the USA was an influential country in this field. Most studies were mainly centered on basic researches in the past decade, and pathways associated with the regulatory role of macrophages in inhibiting and attenuating ALI have become the focus of attention in more recent studies. What is more, our bibliometric analysis showed that macrophages play an important role in COVID-19–induced ALI and may be a target for the treatment of COVID-19.

Effect of methylprednisolone on phospholipase A2 activity and lung surfactant degradation in acute lung injury in rabbits

2001 ◽  
Vol 433 (2-3) ◽  
pp. 209-216 ◽  
Author(s):  
Kenji Kuwabara ◽  
Shingo Furue ◽  
Yasuhiko Tomita ◽  
Masahiko Ueno ◽  
Takashi Ono ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Phospholipase A2 ◽  
Lung Surfactant ◽  
Surfactant Degradation ◽  
Phospholipase A2 Activity
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