Acute and Critical Care

Original Articles

Basic science and research
The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury: Eun-A Jang, Jin-Young Kim, Tran Duc Tin, Ji-A Song, Seong-Heon Lee, Sang-Hyun Kwak; Acute Crit Care. 2019;34(2):133-140. Published online May 31, 2019; DOI: https://doi.org/10.4266/acc.2019.00507

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Background
Overactivation of inflammatory cells, including macrophages and neutrophils, is associated with acute lung injury. BMS-470539 is a selective agonist of melanocortin 1 receptor, which triggers the inhibition of proinflammatory responses, suppressing neutrophil infiltration and protecting tissue. This study evaluated the effects of BMS-470539 on lipopolysaccharide-induced acute lung injury in a mouse model.
Methods
Mice received a subcutaneous injection of saline or BMS-470539 (18.47 mg/kg) 1 hour before an intratracheal injection of saline or lipopolysaccharide (20 μg). Mice were sacrificed to analyze the severity of pulmonary edema (lung wet-to-dry weight [W/D] ratio) and inflammatory responses (level of leukocytes, polymorphonuclear neutrophils [PMNs] and tumor necrosis factor alpha [TNF-α] in bronchoalveolar lavage fluid [BALF]), and neutrophil infiltration (myeloperoxidase activity). TNF-α activation was also measured in neutrophils from bone marrow. Survival was investigated in a second-hit sepsis mouse model.
Results
BMS-470539 improved sepsis-induced pulmonary edema, as demonstrated by a decreased W/D ratio (5.76%±0.83% to 3.81%±0.86%, P<0.05). The inflammatory response also improved, as shown by decreased levels of leukocytes (551±116 to 357±86×10²/mm³, P<0.05), PMNs (51.52%±16.23% to 18.41%±7.25%, P<0.01), and TNF-α (550±338 to 128±52 pg/ml, P<0.01) in the BALF. BMS-470539 also improved the inflammatory response, as shown by TNF-α levels (850±158 to 423±59 pg/ml, P<0.01) in neutrophils. BMS-470539 downregulated neutrophil infiltration in the lung (myeloperoxidase: 654±98 to 218±89 U/g, P<0.001). Lastly, BMS improved the survival rate (0% to 70%, P<0.01) in a mice multiple organ failure model.
Conclusions
BMS-470539 improved lipopolysaccharide-induced acute lung injury and mortality in mice by affecting the inflammatory response.

Citations

Citations to this article as recorded by

Exosomes Derived from ADSCs Attenuate Sepsis-Induced Lung Injury by Delivery of Circ-Fryl and Regulation of the miR-490-3p/SIRT3 Pathway
Weijun Shen, Xuan Zhao, Shitong Li
Inflammation.2022; 45(1): 331. CrossRef
Dichotomous Role of Tumor Necrosis Factor in Pulmonary Barrier Function and Alveolar Fluid Clearance
Rudolf Lucas, Yalda Hadizamani, Perenlei Enkhbaatar, Gabor Csanyi, Robert W. Caldwell, Harald Hundsberger, Supriya Sridhar, Alice Ann Lever, Martina Hudel, Dipankar Ash, Masuko Ushio-Fukai, Tohru Fukai, Trinad Chakraborty, Alexander Verin, Douglas C. Eato
Frontiers in Physiology.2022;[Epub] CrossRef
NDP-MSH treatment recovers marginal lungs during ex vivo lung perfusion (EVLP)
Caterina Lonati, Michele Battistin, Daniele E. Dondossola, Giulia A. Bassani, Daniela Brambilla, Riccardo Merighi, Patrizia Leonardi, Andrea Carlin, Marica Meroni, Alberto Zanella, Anna Catania, Stefano Gatti
Peptides.2021; 141: 170552. CrossRef
Antifibrotic and Anti-Inflammatory Actions of α-Melanocytic Hormone: New Roles for an Old Player
Roshan Dinparastisaleh, Mehdi Mirsaeidi
Pharmaceuticals.2021; 14(1): 45. CrossRef
Activation of Melanocortin Receptors as a Potential Strategy to Reduce Local and Systemic Reactions Induced by Respiratory Viruses
Caterina Lonati, Stefano Gatti, Anna Catania
Frontiers in Endocrinology.2020;[Epub] CrossRef

Basic science and research
Anti-inflammatory Role of Mesenchymal Stem Cells in an Acute Lung Injury Mouse Model: Jin Won Huh, Won Young Kim, Yun Young Park, Chae-Man Lim, Younsuck Koh, Mi-Jung Kim, Sang-Bum Hong; Acute Crit Care. 2018;33(3):154-161. Published online August 31, 2018; DOI: https://doi.org/10.4266/acc.2018.00619

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Abstract PDF Supplementary Material

Background
Mesenchymal stem cells (MSCs) attenuate injury in various lung injury models through paracrine effects. We hypothesized that intratracheal transplantation of allogenic MSCs could attenuate lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice, mediated by anti-inflammatory responses.
Methods
Six-week-old male mice were randomized to either the control or the ALI group. ALI was induced by intratracheal LPS instillation. Four hours after LPS instillation, MSCs or phosphate-buffered saline was randomly intratracheally administered. Neutrophil count and protein concentration in bronchoalveolar lavage fluid (BALF); lung histology; levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and macrophage inflammatory protein-2; and the expression of proliferation cell nuclear antigen (PCNA), caspase-3, and caspase-9 were evaluated at 48 hours after injury.
Results
Treatment with MSCs attenuated lung injury in ALI mice by decreasing protein level and neutrophil recruitment into the BALF and improving the histologic change. MSCs also decreased the protein levels of proinflammatory cytokines including IL-1β, IL-6, and TNF-α, but had little effect on the protein expression of PCNA, caspase-3, and caspase-9.
Conclusions
Intratracheal injection of bone marrow-derived allogenic MSCs attenuates LPSinduced ALI via immunomodulatory effects.

Citations

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The Effectiveness of Adipose Tissue-Derived Mesenchymal Stem Cells Mixed with Platelet-Rich Plasma in the Healing of Inflammatory Bowel Anastomoses: A Pre-Clinical Study in Rats
Georgios Geropoulos, Kyriakos Psarras, Maria Papaioannou, Vasileios Geropoulos, Argyri Niti, Christina Nikolaidou, Georgios Koimtzis, Nikolaos Symeonidis, Efstathios T. Pavlidis, Georgios Koliakos, Theodoros E. Pavlidis, Ioannis Galanis
Journal of Personalized Medicine.2024; 14(1): 121. CrossRef
Cyclic Phytosphingosine-1-Phosphate Primed Mesenchymal Stem Cells Ameliorate LPS-Induced Acute Lung Injury in Mice
Youngheon Park, Jimin Jang, Jooyeon Lee, Hyosin Baek, Jaehyun Park, Sang-Ryul Cha, Se Bi Lee, Sunghun Na, Jae-Woo Kwon, Seok-Ho Hong, Se-Ran Yang
International Journal of Stem Cells.2023; 16(2): 191. CrossRef
Mesenchymal stem cells and their derived exosomes to combat Covid–19
Maryam Yousefi Dehbidi, Nima Goodarzi, Mohammad H. Azhdari, Mohammad Doroudian
Reviews in Medical Virology.2022;[Epub] CrossRef
Stem Cell‐based therapies for COVID‐19‐related acute respiratory distress syndrome
Hoi Wa Ngai, Dae Hong Kim, Mohamed Hammad, Margarita Gutova, Karen Aboody, Christopher D. Cox
Journal of Cellular and Molecular Medicine.2022; 26(9): 2483. CrossRef
Development of a physiomimetic model of acute respiratory distress syndrome by using ECM hydrogels and organ-on-a-chip devices
Esther Marhuenda, Alvaro Villarino, Maria Narciso, Linda Elowsson, Isaac Almendros, Gunilla Westergren-Thorsson, Ramon Farré, Núria Gavara, Jorge Otero
Frontiers in Pharmacology.2022;[Epub] CrossRef
Advances in mesenchymal stromal cell therapy for acute lung injury/acute respiratory distress syndrome
Chang Liu, Kun Xiao, Lixin Xie
Frontiers in Cell and Developmental Biology.2022;[Epub] CrossRef
Auxiliary role of mesenchymal stem cells as regenerative medicine soldiers to attenuate inflammatory processes of severe acute respiratory infections caused by COVID-19
Peyvand Parhizkar Roudsari, Sepideh Alavi-Moghadam, Moloud Payab, Forough Azam Sayahpour, Hamid Reza Aghayan, Parisa Goodarzi, Fereshteh Mohamadi-jahani, Bagher Larijani, Babak Arjmand
Cell and Tissue Banking.2020; 21(3): 405. CrossRef
The Role of MSC Therapy in Attenuating the Damaging Effects of the Cytokine Storm Induced by COVID-19 on the Heart and Cardiovascular System
Georgina M. Ellison-Hughes, Liam Colley, Katie A. O'Brien, Kirsty A. Roberts, Thomas A. Agbaedeng, Mark D. Ross
Frontiers in Cardiovascular Medicine.2020;[Epub] CrossRef

Infection
The Effects of Flecainide Acetate on Inflammatory-Immune Response in Lipopolysaccharide-Stimulated Neutrophils and on Mortality in Septic Rats: Shi Young Chung, Jinyoung Kim, Hong Bum Bae, Tran Duc Tin, Wan Ju, Sang Hyun Kwak; Acute Crit Care. 2018;33(1):34-41. Published online February 28, 2018; DOI: https://doi.org/10.4266/acc.2017.00577

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Abstract PDF

Background
Flecainide acetate is a drug used primarily for cardiac arrhythmia. Some studies also imply that flecainide acetate has the potential to regulate inflammatory-immune responses; however, its mechanism of action is contended. We determined the effects of flecainide acetate on lipopolysaccharide (LPS)-stimulated human neutrophils in vitro and on mortality in a septic rat model.
Methods
Neutrophils from human blood were cultured with varying concentrations of flecainide acetate (1 μM, 10 μM, or 100 μM) with or without LPS (100 ng/ml). To assess neutrophil activation, the protein levels of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and IL-8 were measured after a 4-hour culture period. To assess the intracellular signaling pathways, the levels of phosphorylation of p38 mitogen-activated protein kinase (p38), extracellular signal-regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) were measured after a 30-minute culture period, and the nuclear translocation of nuclear factor (NF)-κB was measured after a 1-hour culture period. Additionally, the survival rate was investigated in a rat sepsis model.
Results
Flecainide acetate down-regulated the activation of proinflammatory cytokines, including TNF-α and IL-6 and IL-8, and intracellular signaling pathways including ERK 1/2 and NF-κB. Flecainide acetate also improved the survival rate in the rat sepsis model.
Conclusions
Collectively, these findings indicate that flecainide acetate can improve survival in a rat sepsis model by attenuating LPS-induced neutrophil responses. We therefore suggest that flecainide acetate plays an important role in modulating inflammatoryimmune responses.

Citations

Citations to this article as recorded by

Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis
Andy Y. An, Arjun Baghela, Peter Zhang, Reza Falsafi, Amy H. Lee, Uriel Trahtemberg, Andrew J. Baker, Claudia C. dos Santos, Robert E. W. Hancock
Frontiers in Immunology.2023;[Epub] CrossRef

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