scholarly journals Neutrophil-Derived IL-17 Promotes Ventilator-Induced Lung Injury via p38 MAPK/MCP-1 Pathway Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoting Liao ◽  
Weikang Zhang ◽  
Huijun Dai ◽  
Ren Jing ◽  
Mengling Ye ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 17 ◽  
Ventilator Induced Lung Injury ◽  
Mitogen Activated Protein

Ventilator-induced lung injury (VILI) is one of the most common complications of mechanical ventilation and can severely affect health. VILI appears to involve excessive inflammatory responses, but its pathogenesis has not yet been clarified. Since interleukin-17 (IL-17) plays a critical role in the immune system and the development of infectious and inflammatory diseases, we investigated here whether it plays a role in VILI. In a mouse model of VILI, mechanical ventilation with high tidal volume promoted the accumulation of lung neutrophils, leading to increased IL-17 levels in the lung, which in turn upregulated macrophage chemoattractant protein-1 via p38 mitogen-activated protein kinase. Depletion of neutrophils decreases the production IL-17 in mice and inhibition of IL-17 significantly reduced HTV-induced lung injury and inflammatory response. These results were confirmed in vitro using RAW264.7 macrophage cultures. Our results suggest that IL-17 plays a pro-inflammatory role in VILI and could serve as a new target for its treatment.

scholarly journals MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity

2018 ◽  
Vol 11 (549) ◽  
pp. eaar3721 ◽  
Author(s):  
Bishuang Cai ◽  
Canan Kasikara ◽  
Amanda C. Doran ◽  
Rajasekhar Ramakrishnan ◽  
Raymond B. Birge ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Gene Encoding ◽  
Endoplasmic Reticulum Calcium ◽  
Calcium Calmodulin Dependent ◽  
Mitogen Activated Protein ◽  
Dependent Protein ◽  
Inflammation Resolution

Inflammation resolution counterbalances excessive inflammation and restores tissue homeostasis after injury. Failure of resolution contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated by endogenous specialized proresolving mediators (SPMs), which are derived from long-chain fatty acids by lipoxygenase (LOX) enzymes. 5-LOX plays a critical role in the biosynthesis of two classes of SPMs: lipoxins and resolvins. Cytoplasmic localization of the nonphosphorylated form of 5-LOX is essential for SPM biosynthesis, whereas nuclear localization of phosphorylated 5-LOX promotes proinflammatory leukotriene production. We previously showed that MerTK, an efferocytosis receptor on macrophages, promotes SPM biosynthesis by increasing the abundance of nonphosphorylated, cytoplasmic 5-LOX. We now show that activation of MerTK in human macrophages led to ERK-mediated expression of the gene encoding sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), which decreased the cytosolic Ca2+ concentration and suppressed the activity of calcium/calmodulin-dependent protein kinase II (CaMKII). This, in turn, reduced the activities of the mitogen-activated protein kinase (MAPK) p38 and the kinase MK2, resulting in the increased abundance of the nonphosphorylated, cytoplasmic form of 5-LOX and enhanced SPM biosynthesis. In a zymosan-induced peritonitis model, an inflammatory setting in which macrophage MerTK activation promotes resolution, inhibition of ERK activation delayed resolution, which was characterized by an increased number of neutrophils and decreased amounts of SPMs in tissue exudates. These findings contribute to our understanding of how MerTK signaling induces 5-LOX–derived SPM biosynthesis and suggest a therapeutic strategy to boost inflammation resolution in settings where defective resolution promotes disease progression.

scholarly journals Ventilator-induced lung-injury in mouse models: Is there a trap?

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Jon Petur Joelsson ◽  
Saevar Ingthorsson ◽  
Jennifer Kricker ◽  
Thorarinn Gudjonsson ◽  
Sigurbergur Karason
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Mouse Models ◽  
Mechanical Strain ◽  
Acute Injury ◽  
In Vivo Studies ◽  
Cellular Interactions ◽  
Ventilator Induced Lung Injury

AbstractVentilator-induced lung injury (VILI) is a serious acute injury to the lung tissue that can develop during mechanical ventilation of patients. Due to the mechanical strain of ventilation, damage can occur in the bronchiolar and alveolar epithelium resulting in a cascade of events that may be fatal to the patients. Patients requiring mechanical ventilation are often critically ill, which limits the possibility of obtaining patient samples, making VILI research challenging. In vitro models are very important for VILI research, but the complexity of the cellular interactions in multi-organ animals, necessitates in vivo studies where the mouse model is a common choice. However, the settings and duration of ventilation used to create VILI in mice vary greatly, causing uncertainty in interpretation and comparison of results. This review examines approaches to induce VILI in mouse models for the last 10 years, to our best knowledge, summarizing methods and key parameters presented across the studies. The results imply that a more standardized approach is warranted.

scholarly journals Inhibition of Poly(Adenosine Diphosphate–Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

2008 ◽  
Vol 108 (2) ◽  
pp. 261-268 ◽  
Author(s):  
Rosanna Vaschetto ◽  
Jan W. Kuiper ◽  
Shyh Ren Chiang ◽  
Jack J. Haitsma ◽  
Jonathan W. Juco ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Tidal Volume ◽  
Interleukin 6 ◽  
Inflammatory Responses ◽  
Adenosine Diphosphate ◽  
High Tidal Volume ◽  
Positive End Expiratory Pressure ◽  
Ventilator Induced Lung Injury ◽  
Pharmacologic Inhibition

Background Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

scholarly journals Adipose-derived exosomes protect the pulmonary endothelial barrier in ventilator-induced lung injury by inhibiting the TRPV4/Ca2+ signaling pathway

2020 ◽  
Vol 318 (4) ◽  
pp. L723-L741 ◽  
Author(s):  
Qian Yu ◽  
Daoxin Wang ◽  
Xiaoting Wen ◽  
Xumao Tang ◽  
Di Qi ◽  
...  
Keyword(s):  
Lung Injury ◽  
Inflammatory Response ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Endothelial Barrier ◽  
Mouse Serum ◽  
Transient Receptor Potential Vanilloid ◽  
Ventilator Induced Lung Injury

Mechanical ventilation (MV) is the main supportive treatment of acute respiratory distress syndrome (ARDS), but it may lead to ventilator-induced lung injury (VILI). Large epidemiological studies have found that obesity was associated with lower mortality in mechanically ventilated patients with acute lung injury, which is known as “obesity paradox.” However, the effects of obesity on VILI are unknown. In the present study, wild-type mice were fed a high-fat diet (HFD) and ventilated with high tidal volume to investigate the effects of obesity on VILI in vivo, and pulmonary microvascular endothelial cells (PMVECs) were subjected to 18% cyclic stretching (CS) to further investigate its underlying mechanism in vitro. We found that HFD protects mice from VILI by alleviating the pulmonary endothelial barrier injury and inflammatory responses in mice. Adipose-derived exosomes can regulate distant tissues as novel adipokines, providing a new mechanism for cell-cell interactions. We extracted three adipose-derived exosomes, including HFD mouse serum exosome (S-Exo), adipose tissue exosome (AT-Exo), and adipose-derived stem cell exosome (ADSC-Exo), and further explored their effects on MV or 18% CS-induced VILI in vivo and in vitro. Administration of three exosomes protected against VILI by suppressing pulmonary endothelial barrier hyperpermeability, repairing the expression of adherens junctions, and alleviating inflammatory response in vivo and in vitro, accompanied by transient receptor potential vanilloid 4 (TRPV4)/Ca2+ pathway inhibition. Collectively, these data indicated that HFD-induced obesity plays a protective role in VILI by alleviating the pulmonary endothelial barrier injury and inflammatory response via adipose-derived exosomes, at least partially, through inhibiting the TRPV4/Ca2+ pathway.

scholarly journals Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation

Science ◽  
2018 ◽  
Vol 361 (6404) ◽  
pp. 810-813 ◽  
Author(s):  
Delphine Cuchet-Lourenço ◽  
Davide Eletto ◽  
Changxin Wu ◽  
Vincent Plagnol ◽  
Olivier Papapietro ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Clinical Symptoms ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Human Immune System ◽  
Hematopoietic Stem ◽  
Kinase Activation ◽  
Protein Kinase Activation ◽  
Mitogen Activated Protein

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.

scholarly journals p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1

2017 ◽  
Vol 217 (1) ◽  
pp. 315-328 ◽  
Author(s):  
Yingli He ◽  
Hua She ◽  
Ting Zhang ◽  
Haidong Xu ◽  
Lihong Cheng ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Morphological Changes ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activity ◽  
Dependent Inhibition ◽  
Mitogen Activated Protein ◽  
P38α Mapk ◽  
Mechanistic Basis

Inflammation and autophagy are two critical cellular processes. The relationship between these two processes is complex and includes the suppression of inflammation by autophagy. However, the signaling mechanisms that relieve this autophagy-mediated inhibition of inflammation to permit a beneficial inflammatory response remain unknown. We find that LPS triggers p38α mitogen-activated protein kinase (MAPK)–dependent phosphorylation of ULK1 in microglial cells. This phosphorylation inhibited ULK1 kinase activity, preventing it from binding to the downstream effector ATG13, and reduced autophagy in microglia. Consistently, p38α MAPK activity is required for LPS-induced morphological changes and the production of IL-1β by primary microglia in vitro and in the brain, which correlates with the p38α MAPK-dependent inhibition of autophagy. Furthermore, inhibition of ULK1 alone was sufficient to promote an inflammatory response in the absence of any overt inflammatory stimulation. Thus, our study reveals a molecular mechanism that enables the initial TLR4-triggered signaling pathway to inhibit autophagy and optimize inflammatory responses, providing new understanding into the mechanistic basis of the neuroinflammatory process.

scholarly journals Alpha 1-antitrypsin ameliorates ventilator-induced lung injury in rats by inhibiting inflammatory responses and apoptosis

2017 ◽  
Vol 243 (1) ◽  
pp. 87-95 ◽  
Author(s):  
He Zhu ◽  
Jianshuai He ◽  
Jia Liu ◽  
Xin Zhang ◽  
Fengyun Yang ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Treatment Options ◽  
Weight Ratio ◽  
Interleukin 10 ◽  
Male Rats ◽  
Ventilator Induced Lung Injury ◽  
Anti Inflammatory ◽  
Alpha 1 Antitrypsin

Mechanical ventilation is extensively used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). The present study investigated the protective effect of alpha 1-antitrypsin (AAT) on VILI. Adult male rats were subjected to sham, ventilation + saline, or ventilation + AAT treatment and lung injuries were evaluated. Peripheral blood and bronchoalveolar lavage fluid (BALF) were obtained to assess systemic and local inflammatory responses, respectively. Mechanical ventilation resulted in lung injury, as evidenced by histological abnormalities as well as elevations in PaO2/FiO2 ratio, the wet-to-dry weight ratio, and the BALF level of proteins. The intravenous administration of AAT significantly improved these parameters of lung function, suggesting a protective role of AAT in VILI. Mechanistically, ventilator-induced inflammation was effectively reduced by AAT, as evidenced by decreases in BALF neutrophil counts, BALF cytokines, and serum adhesion factors. In contrast, anti-inflammatory interleukin-10 in BALF was increased in response to AAT. AAT treatment also inhibited the expression of nuclear factor-κB, Bax, and cleaved caspase-3 while promoting Bcl-2 expression in ventilator-injured lung tissues. AAT treatment can ameliorate VILI by inhibiting inflammatory mediator production and apoptosis. Impact statement Mechanical ventilation has been commonly used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). Few effective treatment options are currently available to reduce VILI. Alpha 1-antitrypsin (AAT) is an inhibitor of serine protease with anti-inflammatory and antiapoptotic properties, suggesting a possible role in attenuating lung injury. The present study demonstrates that AAT inhibits the development of VILI by modulating inflammation- and apoptosis-related protein expression. Therefore, AAT may be a novel therapeutic agent for acute respiratory distress syndrome patients undergoing mechanical ventilation.

scholarly journals Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced lung injury

2012 ◽  
Vol 302 (4) ◽  
pp. L370-L379 ◽  
Author(s):  
Dejie Liu ◽  
Zhibo Yan ◽  
Richard D. Minshall ◽  
David E. Schwartz ◽  
Yuguo Chen ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Tidal Volume ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Neutrophil Recruitment ◽  
Calpain Activation ◽  
Ventilator Induced Lung Injury ◽  
Volume Ventilation ◽  
Calpain 2

Lung inflammatory responses in the absence of infection are considered to be one of primary mechanisms of ventilator-induced lung injury. Here, we determined the role of calpain in the pathogenesis of lung inflammation attributable to mechanical ventilation. Male C57BL/6J mice were subjected to high (28 ml/kg) tidal volume ventilation for 2 h in the absence and presence of calpain inhibitor I (10 mg/kg). To address the isoform-specific functions of calpain 1 and calpain 2 during mechanical ventilation, we utilized a liposome-based delivery system to introduce small interfering RNAs targeting each isoform in pulmonary vasculature in vivo. Mechanical ventilation with high tidal volume induced rapid (within minutes) and persistent calpain activation and lung inflammation as evidenced by neutrophil recruitment, production of TNF-α and IL-6, pulmonary vascular hyperpermeability, and lung edema formation. Pharmaceutical calpain inhibition significantly attenuated these inflammatory responses caused by lung hyperinflation. Depletion of calpain 1 or calpain 2 had a protective effect against ventilator-induced lung inflammatory responses. Inhibition of calpain activity by means of siRNA silencing or pharmacological inhibition also reduced endothelial nitric oxide (NO) synthase (NOS-3)-mediated NO production and subsequent ICAM-1 phosphorylation following high tidal volume ventilation. These results suggest that calpain activation mediates early lung inflammation during ventilator-induced lung injury via NOS-3/NO-dependent ICAM-1 phosphorylation and neutrophil recruitment. Inhibition of calpain activation may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury.

scholarly journals Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection.

1998 ◽  
Vol 9 (8) ◽  
pp. 1526-1534
Author(s):  
C Van Kooten ◽  
J G Boonstra ◽  
M E Paape ◽  
F Fossiez ◽  
J Banchereau ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Inflammatory Responses ◽  
Biological Activities ◽  
Critical Role ◽  
Interleukin 17 ◽  
Tubular Epithelial Cells ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Local production of cytokines plays a critical role in the regulation of pathophysiologic processes leading to rejection of transplanted organs. In the present study, the possible role of interleukin-17 (IL-17), a recently identified cytokine with unique properties, was investigated. IL-17 is specifically produced by activated T cells, whereas biological activities are restricted to the activation of nonhematopoietic cells. In vitro, IL-17 induced primary human proximal tubular epithelial cells, a type of cell regulating local interstitial inflammatory responses, to secrete higher levels of IL-6, IL-8, and monocyte chemoattractant protein-1, but not of the chemokine RANTES. The effect was specific for IL-17, because it was completely abrogated by a neutralizing anti-IL-17 antibody and was demonstrated to be dose- and time-dependent. In addition, IL-17 increased the production of complement component C3 by human proximal tubular epithelial cells, but not of other complement components. Immunofluorescence showed expression of IL-17 in kidney biopsies from patients suffering from graft rejection (8 of 8 positive), whereas pretransplant biopsies and normal kidneys were negative (0 of 6). Analysis of whole kidney isolates confirmed the presence of IL-17 mRNA by reverse transcription-PCR. IL-17 expression could also be found in in vitro cultured and activated graft-infiltrating T cells. These results represent the first demonstration of IL-17 protein expression in pathologic conditions and suggest that IL-17 might be important in the regulation of local inflammatory responses.

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