scholarly journals Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury

2018 ◽  
Vol 51 (6) ◽  
pp. 2776-2793 ◽  
Author(s):  
Yung-Fong Tsai ◽  
Shun-Chin Yang ◽  
Wen-Yi Chang ◽  
Jih-Jung Chen ◽  
Chun-Yu Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Superoxide Anion ◽  
Calcium Influx ◽  
Neutrophil Activation ◽  
Lung Damage ◽  
Hek293 Cells ◽  
Human Neutrophils ◽  
Therapeutic Effects

Background/Aims: Formyl peptide receptors (FPRs) recognize different endogenous and exogenous molecular stimuli and mediate neutrophil activation. Dysregulation of excessive neutrophil activation and the resulting immune responses can induce acute lung injury (ALI) in the host. Accordingly, one promising approach to the treatment of neutrophil-dominated inflammatory diseases involves therapeutic FPR1 inhibition. Methods: We extracted a potent FPR1 antagonist from Garcinia multiflora Champ. (GMC). The inhibitory effects of GMC on superoxide anion release and elastase degranulation from activated human neutrophils were determined with spectrophotometric analysis. Reactive oxygen species (ROS) production and the FPR1 binding ability of neutrophils were assayed by flow cytometry. Signaling transduction mediated by GMC in response to chemoattractants was assessed with a calcium influx assay and western blotting. A lipopolysaccharide (LPS)-induced ALI mouse model was used to determine the therapeutic effects of GMC in vivo. Results: GMC significantly reduced superoxide anion release, the reactive oxidants derived therefrom, and elastase degranulation mediated through selective, competitive FPR1 blocking in N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)-stimulated human neutrophils. In cell-free systems, GMC was unable to scavenge superoxide anions or suppress elastase activity. GMC produced a right shift in fMLF-activated concentration-response curves and was confirmed to be a competitive FPR1 antagonist. GMC binds to FPR1 not only in neutrophils, but also FPR1 in neutrophil-like THP-1 and hFPR1-transfected HEK293 cells. Furthermore, the mobilization of calcium and phosphorylation of mitogen-activated protein kinases and Akt, which are involved in FPR1-mediated downstream signaling, was competitively blocked by GMC. In an in vivo study, GMC significantly reduced pulmonary edema, neutrophil infiltration, and alveolar damage in LPS-induced ALI mice. Conclusion: Our findings demonstrate that GMC is a natural competitive FPR1 inhibitor, which makes it a possible anti-inflammatory treatment option for patients critically inflicted with FPR1-mediated neutrophilic lung damage.

Identification of a Two-Step Mechanism Responsible for Antibody-Mediated Transfusion Related Acute Lung Injury (TRALI)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 846-846
Author(s):  
Christopher G.J. McKenzie ◽  
Michael Kim ◽  
Tarandeep Singh ◽  
John W. Semple
Keyword(s):  
Reactive Oxygen Species ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Mhc Class I ◽  
Reactive Oxygen ◽  
Lung Damage ◽  
Class I ◽  
Oxygen Species ◽  
Neutrophil Accumulation

Abstract Abstract 846 Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion fatalities, and most TRALI reactions are thought to be caused by donor antibodies. It is currently thought that the donor antibodies activate pulmonary neutrophils to produce reactive oxygen species that damage lung tissue. There have been several animal models of TRALI developed including, for example, ex vivo lung models demonstrating the importance of human anti-neutrophil antibodies in TRALI, and in vivo models showing how biological response modifiers can induce recipient lung damage. An in vivo murine model of antibody-mediated TRALI was developed in 2006, and has also shown several similarities with human TRALI induction (Looney MR et al., J Clin Invest 116: 1615, 2006). Specifically, a monoclonal anti-mouse MHC class I antibody (34-1-2s) causes significant increases in excess lung water, lung vascular permeability and mortality within 2 hours after administration. These adverse reactions were found to be due to the antibody's ability to activate pulmonary neutrophils to produce reactive oxygen species (ROS) in an Fc receptor (FcR)-dependent manner. In contrast, however, it was recently shown that 34-1-2s induces pulmonary damage by activating macrophages to generate ROS in a complement (C5a)-dependent process (Strait RT J et al., Exp Med 208: 2525, 2011). In order to better understand this apparent controversy, we attempted to determine the nature of how 34-1-2s mediates its lung damaging properties. 34-1-2s was digested with pepsin or papain to produce F(ab')2 or Fc fragments respectively, and the fragments were tested for their ability to mediate TRALI reactions. In control mice, when intact 34-1-2s antibody was intravenously injected into either CB.17 mice with severe combined immunodeficiency or C5 deficient DBA/2 mice, increased shock, serum MIP-2 (murine equivalent to human IL-8) levels, pulmonary neutrophil accumulation, pulmonary edema and mortality all occurred within 2 hours. In contrast, however, injection with 34-1-2s F(ab')2 fragments was only able to generate MIP-2 production and pulmonary neutrophil accumulation; no lung damage or mortality occurred. Injection of 34-1-2s Fc fragments either alone or together with equal molar concentrations of F(ab')2 fragments failed to induce any lung damage or mortality. These results suggest that 34-1-2s recognition of it's cognate MHC class I antigen may be a priming reaction that stimulates MIP-2 and chemotaxis of neutrophils to the lungs, whereas the Fc portion of the intact molecule is responsible for the second step of exacerbating TRALI symptoms in a complement independent manner. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Baicalin Liposome Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice via Inhibiting TLR4/JNK/ERK/NF-κB Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yu Long ◽  
Yan Xiang ◽  
Songyu Liu ◽  
Yulu Zhang ◽  
Jinyan Wan ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Injury Score ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Scutellaria Baicalensis Georgi ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Novel Drug

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are challenging diseases with the high mortality in a clinical setting. Baicalin (BA) is the main effective constituent isolated from the Chinese medical herb Scutellaria baicalensis Georgi, and studies have proved that it has a protective effect on ALI induced by lipopolysaccharide (LPS) due to the anti-inflammatory efficacy. However, BA has low solubility which may limit its clinical application. Hence, we prepared a novel drug delivery system—Baicalin liposome (BA-LP) in previous research—which can improve some physical properties of BA. Therefore, we aimed to explore the effect of BA-LP on ALI mice induced by LPS. In pharmacokinetics study, the values of t 1 / 2 and AUC0- t in the BA-LP group were significantly higher than that of the BA group in normal mice, indicating that BA-LP could prolong the duration time in vivo of BA. The BA-LP group also showed a higher concentration in lung tissues than the BA group. Pharmacodynamics studies showed that BA-LP had a better effect than the BA group at the same dosage on reducing the W/D ratio, alleviating the lung injury score, and decreasing the proinflammatory factors (TNF-α, IL-1β) and total proteins in bronchoalveolar lavage fluids (BALF). In addition, the therapeutic effects of BA-LP showed a dose-dependent manner. Western blot analysis indicated that the anti-inflammatory action of BA could be attributed to the inhibition of the TLR4-NFκBp65 and JNK-ERK signaling pathways. These results suggest that BA-LP could be a valuable therapeutic candidate in the treatment of ALI.

scholarly journals α-Mangostin Alleviated Lipopolysaccharide Induced Acute Lung Injury in Rats by Suppressing NAMPT/NAD Controlled Inflammatory Reactions

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Mengqing Tao ◽  
Jia Jiang ◽  
Lin Wang ◽  
Yan Li ◽  
Qingcheng Mao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Raw 264.7 Cells ◽  
Therapeutic Effects ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Inflammatory Reactions ◽  
Hematological Analysis ◽  
Underlying Mechanisms

α-Mangostin (MAN) is a bioactive xanthone isolated from mangosteen. This study was designed to investigate its therapeutic effects on acute lung injury (ALI) and explore the underlying mechanisms of action. Rats from treatment groups were subject to oral administration of MAN for 3 consecutive days beforehand, and then ALI was induced in all the rats except for normal controls via an intraperitoneal injection with lipopolysaccharide. The severity of disease was evaluated by histological examination and hematological analysis. Protein expressions in tissues and cells were examined with immunohistochemical and immunoblotting methods, respectively. The levels of cytokines and nicotinamide adenine dinucleotide (NAD) were determined using ELISA and colorimetric kits, respectively. It was found that MAN treatment significantly improved histological conditions, reduced leucocytes counts, relieved oxidative stress, and declined TNF-α levels in ALI rats. Meanwhile, MAN treatment decreased expressions of nicotinamide phosphoribosyltransferase (NAMPT) and Sirt1 both in vivo and in vitro, which was accompanied with a synchronized decline of NAD and TNF-α. Immunoblotting assay further showed that MAN downregulated HMGB1, TLR4, and p-p65 in RAW 264.7 cells. MAN induced declines of both HMGB1/TLR4/p-p65 and TNF-α were substantially reversed by cotreatment with nicotinamide mononucleotide or NAD. These results suggest that downregulation of NAMPT/NAD by MAN treatments contributes to the alleviation of TLR4/NF-κB-mediated inflammations in macrophage, which is essential for amelioration of ALI in rats.

Bactericidal/permeability-increasing protein ameliorates acute lung injury in porcine endotoxemia

1994 ◽  
Vol 76 (5) ◽  
pp. 2006-2014 ◽  
Author(s):  
T. J. Vandermeer ◽  
M. J. Menconi ◽  
B. P. O′Sullivan ◽  
V. A. Larkin ◽  
H. Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Human Neutrophils ◽  
Cationic Protein ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
To Receive ◽  
Necrosis Factor

Bactericidal/permeability-increasing protein (BPI), a cationic protein isolated from human neutrophils, binds lipopolysaccharide (LPS), kills gram-negative bacteria, and neutralizes many of the effects of LPS in vitro and in vivo. We hypothesized that a recombinant 23-kDa NH2-terminal fragment of BPI (BPI23) would reduce acute lung injury in endotoxemic pigs. At -18 h, pigs received an intravenous priming dose of LPS (20 micrograms/kg). Anesthetized ventilated swine were randomized to receive 1) no further treatment (n = 4); 2) LPS (250 micrograms/kg over 50 min) and BPI23 (3-mg/kg bolus and 3 mg/kg over 60 min) (n = 6); or 3) LPS and thaumatin, a cationic protein devoid of LPS neutralizing activity that has a molecular mass and isoelectric point that are similar to that of BPI23 (n = 7). BPI23 treatment significantly ameliorated LPS-induced hypoxemia, functional upregulation of opsonin receptors on circulating phagocytes, and alveolitis but had no effect on the elaboration of tumor necrosis factor-alpha or thromboxane A2. The salutory effects of BPI23 on acute lung injury in endotoxemic pigs may be mediated, at least in part, by inhibition of direct activation of phagocytes by LPS.

scholarly journals miR-20b suppresses mitochondrial dysfunction–mediated apoptosis to alleviate hyperoxia-induced acute lung injury by directly targeting MFN1 and MFN2

2020 ◽  
Author(s):  
Genhua Mu ◽  
Yijun Deng ◽  
Zhongqian Lu ◽  
Xing Li ◽  
Yanbin Chen
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cell Apoptosis ◽  
Prolonged Exposure ◽  
Biological Effects ◽  
Pulmonary Inflammation ◽  
Alveolar Epithelial Cells ◽  
Lung Damage

Abstract Supplemental oxygen is commonly used to treat severe respiratory failure, while prolonged exposure to hyperoxia can induce acute lung injury characterized by the accumulation of reactive oxygen species (ROS) and pulmonary inflammation. Dysregulation of microRNAs contributes to multiple diseases, including hyperoxia-induced acute lung injury (HALI). In this study, we explored the roles of miR-20b in mediating the response of type II alveolar epithelial cells (ACE IIs) to hyperoxia and the potential underlying mechanisms. We found that miR-20b was significantly decreased in the lung tissues of HALI models and H2O2-treated ACE IIs. Hyperoxia induced the release of TNF-α, decreased the mitochondrial membrane potential, and led to excessive ROS production and cell apoptosis. Overexpression of miR-20b suppressed the hyperoxia-induced biological effects in ACE IIs. miR-20b negatively regulated the expression levels of Mitofusin 1 (MFN1) and MFN2, the two key proteins of mitochondrial fusion, via complementarily binding to the 3ʹ-untranslated regions of mRNAs. Furthermore, both in vivo and in vitro, upregulation of MFN1 and MFN2 aggravated lung damage and cell apoptosis that were alleviated by miR-20b overexpression. These results provided new insights into the involvement of the miR-20b/MFN1/2 signaling pathway in HALI.

scholarly journals Alveolar Type II Cells or Mesenchymal Stem Cells: Comparison of Two Different Cell Therapies for the Treatment of Acute Lung Injury in Rats

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1816
Author(s):  
Raquel Guillamat-Prats ◽  
Marta Camprubí-Rimblas ◽  
Ferranda Puig ◽  
Raquel Herrero ◽  
Neus Tantinyà ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Molecular Mechanisms ◽  
Lung Damage ◽  
Alveolar Type ◽  
Therapeutic Effects ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Type Ii Cells ◽  
Cell Therapies

The use of cell therapies has recently increased for the treatment of pulmonary diseases. Mesenchymal stem/stromal cells (MSCs) and alveolar type II cells (ATII) are the main cell-based therapies used for the treatment of acute respiratory distress syndrome (ARDS). Many pre-clinical studies have shown that both therapies generate positive outcomes; however, the differences in the efficiency of MSCs or ATII for reducing lung damage remains to be studied. We compared the potential of both cell therapies, administering them using the same route and dose and equal time points in a sustained acute lung injury (ALI) model. We found that the MSCs and ATII cells have similar therapeutic effects when we tested them in a hydrochloric acid and lipopolysaccharide (HCl-LPS) two-hit ALI model. Both therapies were able to reduce proinflammatory cytokines, decrease neutrophil infiltration, reduce permeability, and moderate hemorrhage and interstitial edema. Although MSCs and ATII cells have been described as targeting different cellular and molecular mechanisms, our data indicates that both cell therapies are successful for the treatment of ALI, with similar beneficial results. Understanding direct cell crosstalk and the factors released from each cell will open the door to more accurate drugs being able to target specific pathways and offer new curative options for ARDS.

scholarly journals MicroRNA-377-3p released by mesenchymal stem cell exosomes ameliorates lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy

2020 ◽  
Vol 11 (8) ◽  
Author(s):  
Xuxia Wei ◽  
Xiaomeng Yi ◽  
Haijin Lv ◽  
Xin Sui ◽  
Pinglan Lu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Fetal Lung ◽  
Lung Damage ◽  
Inflammatory Factors ◽  
Human Umbilical Cord ◽  
Human Fetal Lung ◽  
Human Fetal Lung Fibroblast

Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the severe lung damage and respiratory failure without effective therapy. However, there was a lack of understanding of the mechanism by which exosomes regulate autophagy during ALI/ARDS. Here, we found lipopolysaccharide (LPS) significantly increased inflammatory factors, administration of exosomes released by human umbilical cord mesenchymal stem cells (hucMSCs) successfully improved lung morphometry. Further studies showed that miR-377-3p in the exosomes played a pivotal role in regulating autophagy, leading to protect LPS induced ALI. Compared to exosomes released by human fetal lung fibroblast cells (HFL-1), hucMSCs-exosomes overexpressing miR-377-3p more effectively suppressed the bronchoalveolar lavage (BALF) and inflammatory factors and induced autophagy, causing recoveration of ALI. Administration of miR-377-3p expressing hucMSCs-exosomes or its target regulatory-associated protein of mTOR (RPTOR) knockdown significantly reduced ALI. In summary, miR-377-3p released by hucMSCs-exosomes ameliorated Lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy in vivo and in vitro.

Pulmonary angiotensin-converting enzyme kinetics after acute lung injury in the rabbit

1988 ◽  
Vol 64 (6) ◽  
pp. 2508-2516 ◽  
Author(s):  
D. Riggs ◽  
A. M. Havill ◽  
B. R. Pitt ◽  
C. N. Gillis
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Angiotensin Converting Enzyme ◽  
Lung Damage ◽  
Converting Enzyme ◽  
Intratracheal Administration ◽  
Multiple Indicator Dilution ◽  
Before And After ◽  
High Doses

Depression of lung endothelial cell metabolic function may be an early and sensitive indicator of lung damage. When such functions are measured in vivo, substrates injected usually must be limited to "trace" doses due to the significant hemodynamic effects of high doses of substrate. Under first-order conditions (i.e., trace doses) the enzyme or transport system rate constant Vmax/Km may be calculated, but independent estimates of each variable (Vmax and Km) are not available. We therefore used multiple indicator-dilution methods and higher substrate concentrations to apply a mathematical model, based on saturable kinetics that yield independent estimates of the apparent kinetic parameters Vmax and Km for pulmonary angiotensin-converting enzyme (ACE). We used the ACE substrate, [3H]benzoyl-phenylalanyl-alanyl-proline ([3H]BPAP) and made these measurements and also estimates of serotonin [5-hydroxytryptamine (5-HT)] removal, before and after acute lung injury induced by intratracheal administration of phorbol myristate acetate (PMA). PMA significantly depressed the percent 5-HT removal (62 +/- 3 to 44 +/- 4%) and BPAP percent metabolism (74 +/- 2 to 66 +/- 2), when trace amounts of either compound were injected as a bolus.

scholarly journals C-reactive protein enhances murine antibody–mediated transfusion-related acute lung injury

Blood ◽  
2015 ◽  
Vol 126 (25) ◽  
pp. 2747-2751 ◽  
Author(s):  
Rick Kapur ◽  
Michael Kim ◽  
Shanjeevan Shanmugabhavananthan ◽  
Jonathan Liu ◽  
Yuan Li ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Damage ◽  
C Reactive Protein ◽  
Neutrophil Accumulation ◽  
Reactive Protein ◽  
Key Points ◽  
Synergistic Increase ◽  
Murine Antibody

Key Points CRP enhances antibody-mediated lung damage when infused into TRALI-resistant mice. CRP and TRALI-inducing antibodies generate a synergistic increase in MIP-2 production and pulmonary neutrophil accumulation in vivo.

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