Acute and Critical Care

Original Articles

Neurology
Cytokine profiles in intensive care unit delirium: Ryan J. Smith, Christian Lachner, Vijay P. Singh, Shubham Trivedi, Biswajit Khatua, Rodrigo Cartin-Ceba; Acute Crit Care. 2022;37(3):415-428. Published online June 20, 2022; DOI: https://doi.org/10.4266/acc.2021.01508

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Background
Neuroinflammation causing disruption of the blood-brain barrier and immune cell extravasation into the brain parenchyma may cause delirium; however, knowledge of the exact pathophysiologic mechanism remains incomplete. The purpose of our study was to determine whether cytokine profiles differ depending on whether delirium occurs in the setting of sepsis, coronavirus disease 2019 (COVID-19), or recent surgery.
Methods
This prospective observational cohort study involved 119 critically ill patients admitted to a multidisciplinary intensive care unit (ICU) during 2019 and 2020. Delirium was identified using the validated confusion assessment method for the ICU. Multiple delirium risk factors were collected daily including clinical characteristics, hospital course, lab values, vital signs, surgical exposure, drug exposure, and COVID-19 characteristics. Serums samples were collected within 12 hours of ICU admission and cytokine levels were measured.
Results
The following proinflammatory cytokines were elevated in our delirium population: tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-18, C-C motif ligand (CCL) 2, CCL3, C-X-C motif chemokine ligand (CXCL)1, CXCL10, IL-8, IL-1 receptor antagonist, and IL-10. Analysis of relative cytokine levels in those patients that developed delirium in the setting of sepsis, COVID-19, and recent surgery showed elevations of CCL2, CXCL10, and TNF-α in both the sepsis and COVID-19 group in comparison to the postsurgical population. In the postsurgical group, granulocyte colony-stimulating factor was elevated and CXCL10 was decreased relative to the opposing groups.
Conclusions
We identify several cytokines and precipitating factors known to be associated with delirium. However, our study suggests that the cytokine profile associated with delirium is variable and contingent upon delirium precipitating factors.

Citations

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Association of postoperative delirium with serum and cerebrospinal fluid proteomic profiles: a prospective cohort study in older hip fracture patients
Lucía Lozano-Vicario, Ángel Javier Muñoz-Vázquez, Robinson Ramírez-Vélez, Arkaitz Galbete-Jiménez, Joaquín Fernández-Irigoyen, Enrique Santamaría, Bernardo Abel Cedeno-Veloz, Fabricio Zambom-Ferraresi, Barbara C. Van Munster, José Ramón Ortiz-Gómez, Ángel
GeroScience.2024; 46(3): 3235. CrossRef
Association of peripheral B cells and delirium: combined single-cell sequencing and Mendelian randomization analysis
Siyou Tan, Sining Pan, Lai Wei, Wenyan Chen, Bingbing Pan, Gaoyin Kong, Jing Chen, Yubo Xie
Frontiers in Neurology.2024;[Epub] CrossRef
Brain injury biomarkers do not predict delirium in acutely ill older patients: a prospective cohort study
Júlio César Garcia de Alencar, Flávia Barreto Garcez, Agnes Araujo Sardinha Pinto, Lucas Oliveira Junqueira e Silva, Lucas de Moraes Soler, Shirley Steffany Muñoz Fernandez, Victor Van Vaisberg, Luz Marina Gomez Gomez, Sandra Maria Lima Ribeiro, Thiago Ju
Scientific Reports.2023;[Epub] CrossRef
Systemic interleukin-6 inhibition ameliorates acute neuropsychiatric phenotypes in a murine model of acute lung injury
Faizan Anwar, Nicklaus A. Sparrow, Mohammad Harun Rashid, Gena Guidry, Michael M. Gezalian, Eric J. Ley, Maya Koronyo-Hamaoui, Itai Danovitch, E. Wesley Ely, S. Ananth Karumanchi, Shouri Lahiri
Critical Care.2022;[Epub] CrossRef

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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Abstract PDF

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

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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

Effect of Caffeic Acid Phenethyl Ester on Lipopolysaccharide-induced Murine Macrophage Activation: Seong Heon Lee, Mei Li, Dae Wook Lee, Dong Yun Lim, Cheol Won Jeong, Sang Hyun Kwak; Korean J Crit Care Med. 2011;26(3):134-138.; DOI: https://doi.org/10.4266/kjccm.2011.26.3.134

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Abstract PDF: BACKGROUND
Caffeic acid phenethyl ester (CAPE) is an active component of propolis and is known to have anti-inflammatory properties. This study was performed to evaluate the effects of CAPE on lipopolysaccharide (LPS)-induced murine macrophage activation.
METHODS
Raw 264.7 cells were incubated with varying concentrations of CAPE with or without LPS. The production of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and macrophage inflammatory protein-2 (MIP-2) and activation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun amino terminal kinases (JNK) and p38 were measured.
RESULTS
CAPE inhibited the production of TNF-alpha, IL-1beta and MIP-2 and attenuated phosphorylation levels of ERK1/2 and p38, but not JNK in RAW264.7 cells stimulated with LPS.
CONCLUSIONS
CAPE can attenuate LPS-induced macrophage responses and we suggest that these effects may play an important role in modulating macrophage-mediated inflammatory responses in vivo.

Association of Hyperlactatemia and IL-6 Hypercytokinemia after Cardiopulmonary Bypass: A Preliminary Report: Sang Hoon Yoon, Seung Zhoo Yoon, Hye Won Shin, Sung Uk Choi, Choon Hak Lim; Korean J Crit Care Med. 2011;26(1):18-23.; DOI: https://doi.org/10.4266/kjccm.2011.26.1.18

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Abstract PDF: BACKGROUND
In cardiac surgery with cardiopulmonary bypass (CPB), hyperlactatemia (HL) is common and is associated with postoperative morbidity and mortality. At present, the cause of HL during CPB is proposed to be tissue hypoxia. Tissue perfusion and oxygen delivery can be impaired to varying degrees during CPB. Although surgery involving CPB apparatus is associated with increased pro-inflammatory mediators, such as TNF-alpha and IL-6, tissue hypoxia that occurs during CPB may be an additionally potent stimulus to inflammation. We hypothesized that hypoxic patients during CPB that experience elevated serum lactate levels, may be related to higher serum cytokine level after CPB than normoxic patients during CPB with normal serum lactate levels.
METHODS
Levels of TNF-alpha and IL-6 were measured by ELISA in a) Time 1; before initiation of CPB, b) Time 2; 30 min after aortic de-clamping, c) Time 3; 24 hrs after aortic de-clamping. Levels of lactate was measured at a) Time A; before initiation of CPB, b) Time B; 30 min after aortic de-clamping. Postoperative ICU stay, intubation time and oxygen index were evaluated as postoperative morbidity scale.
RESULTS
There were no statistical differences between HL (n = 43, lactate > or =3 mMol/L at time B) and normal lactate group (NL) (n = 63, lactate <3 mMol/L at time B) in demographic data, preoperative left ventricular ejection fraction, CPB time, and aortic cross-clamp time. Level of IL-6 in HL at time 3 was higher than that of NL. The ICU stay and intubation time were longer in HL. The oxygen index on 1st postoperative day was lower in HL.
CONCLUSIONS
Our results suggest that hyperlactatemia after weaning from CPB may be related to IL-6 hypercytokinemia, and therefore related to postoperative morbidity.

The Effect of Itraconazole Pretreatment in Lipopolysaccharide-Induced Acute Lung Injury in Rats: Tae Rim Shin, Young Man Lee, Younsuck Koh; Korean J Crit Care Med. 2010;25(3):149-154.; DOI: https://doi.org/10.4266/kjccm.2010.25.3.149

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Abstract PDF

BACKGROUND
Despite the fact that a randomized controlled trial did not support the use of ketoconazole for treatment of acute lung injury (ALI), there is evidence that pretreatment with ketoconazole might prevent ALI in critically ill patients. An in vitro study showed, however, that itraconazole was a more potent inhibitor of thromboxane and leukotriene formation than was ketoconazole. We investigated the effect of itraconazole pretreatment in lipopolysaccharide (LPS)-induced ALI in rats.
METHODS
Twenty-one pathogen free, male Sprague-Dawley rats were administered either saline or LPS (5 mg/kg of body weight) intratracheally, with or without intraperitoneal pretreatment of itraconazole (2.5 mg/kg). Six hours after saline or LPS treatment (7 h after itraconazole pretreatment), samples were obtained.
RESULTS
Compared with the saline group, LPS group had increased total cell count, polymorphonuclear leukocyte differential count, protein, lactate dehydrogenase (LDH) and cytokines in BAL fluid. Itraconazole pretreatment decreased polymrphonuclear leukocyte differential count, protein and LDH in BAL fluid compared with those of LPS-treated rats without itraconazole pretreatment. Itraconazole pretreatment also decreased the elevated BAL fluid levels of interleukin-1beta (IL-1beta) and cytokine-induced neutrophil chemoattractant (CINC) by LPS. There was, however, no difference in the BAL fluid tumor necrosis factor alpha (TNF-alpha) level in terms of itraconazole pretreatment in LPS-treated rats. Histopathologic features of LPS-induced ALI were attenuated by itraconazole pretreatment.
CONCLUSIONS
These results suggest that itraconazole pretreatment attenuated LPS-induced ALI in rats. Decreases in levels of IL-1beta and CINC would likely be associated with attenuation of LPS-induced ALI in rats by itraconazole pretreatment.

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Itraconazole-Loaded Ufasomes: Evaluation, Characterization, and Anti-Fungal Activity against Candida albicans
Sara M. Hashem, Mary K. Gad, Hend M. Anwar, Neveen M. Saleh, Rehab N. Shamma, Noha I. Elsherif
Pharmaceutics.2022; 15(1): 26. CrossRef

Review

Inflammation and Sepsis: Ji Young Yoon, Jae Young Kwon; Korean J Crit Care Med. 2010;25(1):1-8.; DOI: https://doi.org/10.4266/kjccm.2010.25.1.1

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Abstract PDF

Despite the development of modern intensive care and new antimicrobial agents, the mortality of the patients with severe sepsis and septic shock remains high. The poor outcome is considered to be a consequence of an overactive systemic inflammatory response. Sepsis is now defined as systemic inflammatory response syndrome (SIRS) in which there is an identifiable focus of infection. As a consequence of the overactive SIRS response, the function of various organ systems may be compromised, resulting in multiple organ dysfunction syndrome (MODS) and death. Systemic inflammation is a consequence of activation of the innate immune system. It is characterized by intravascular release of pro-inflammatory cytokines and other vasoactive mediators, and the concurrent activation of the innate immune cells. In addition to the pro-inflammatory reactions, the host's anti-inflammatory mechanisms are also activated and aimed at counteracting the inflammatory response. The balance between pro- and anti-inflammatory reactions is critical for the outcome of the patient. Understanding the mechanisms of acute inflammatory responses in critical ill patients is necessary for the development of urgently needed therapeutics. The aim of this review is to provide a description of the key components and mechanisms involved in the inflammatory response in patients with SIRS and sepsis.

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