Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge

2006 ◽  
Vol 290 (1) ◽  
pp. L51-L58 ◽  
Author(s):  
Joanne Lomas-Neira ◽  
Chun-Shiang Chung ◽  
Mario Perl ◽  
Stephen Gregory ◽  
Walter Biffl ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Tissue ◽  
Peripheral Blood ◽  
Lavage Fluid ◽  
Tissue Samples ◽  
Relative Contribution ◽  
Inflammatory Protein ◽  
Tnf Α ◽  
Pulmonary Macrophages

Acute lung injury (ALI) is identified with the targeting/sequestration of polymorphonuclear leukocytes (PMN) to the lung. Instrumental to PMN targeting are chemokines [e.g., macrophage inflammatory protein-2 (MIP-2), keratinocyte-derived chemokine (KC), etc.] produced by macrophage, PMN, and other resident pulmonary cells. However, the relative contribution of resident pulmonary macrophages as opposed to PMN in inducing ALI is poorly understood. We therefore hypothesize that depletion of peripheral blood PMN and/or the oblation of a macrophage-mediated PMN chemokine signal (via macrophage deficiency) will reduce the inflammation and ALI observed in mice following hemorrhage (Hem) and subsequent sepsis (CLP) in our murine model of ALI. To examine this we pretreated mice with either 500 μg anti-mouse Gr1 antibody/animal (to deplete PMN) or subjected mice deficient in mature macrophage (B6C3Fe-a/a-CsF1op) to Hem (90 min at 35 ± 5 mmHg) followed by resuscitation. Twenty-four hours post-Hem, mice were subjected to CLP and killed 24 h later, and lung tissue samples were collected. Our data showed that in the absence of either peripheral blood PMN or mature tissue macrophages there was a suppression of IL-6, KC, and MIP-2 levels in lung tissue from Hem/CLP mice as well as a reduction in PMN influx to the lung and lung injury (bronchoalveolar lavage fluid protein). In contrast, lung tissue IL-10 and TNF-α levels were suppressed in the macrophage-deficient Hem/CLP mice compared with PMN-depleted Hem/CLP mice. Together, these data suggest that both the PMN and the macrophage are required to induce inflammation seen here, however, macrophage not PMN regulate the release of IL-10, independent of local changes in TNF.

scholarly journals Mibefradil and Flunarizine, Two T-Type Calcium Channel Inhibitors, Protect Mice against Lipopolysaccharide-Induced Acute Lung Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Limei Wan ◽  
Weibin Wu ◽  
Shunjun Jiang ◽  
Shanhe Wan ◽  
Dongmei Meng ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Calcium Channel ◽  
Lavage Fluid ◽  
Cell Number ◽  
Effector Cells ◽  
Potent Inhibition ◽  
Tnf Α ◽  
Calcium Channel Inhibitors

Recent studies have illuminated that blocking Ca2+ influx into effector cells is an attractive therapeutic strategy for lung injury. We hypothesize that T-type calcium channel may be a potential therapeutic target for acute lung injury (ALI). In this study, the pharmacological activity of mibefradil (a classical T-type calcium channel inhibitor) was assessed in a mouse model of lipopolysaccharide- (LPS-) induced ALI. In LPS challenged mice, mibefradil (20 and 40 mg/kg) dramatically decreased the total cell number, as well as the productions of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Mibefradil also suppressed total protein concentration in BALF, attenuated Evans blue extravasation, MPO activity, and NF-κB activation in lung tissue. Furthermore, flunarizine, a widely prescripted antimigraine agent with potent inhibition on T-type channel, was also found to protect mice against lung injury. These data demonstrated that T-type calcium channel inhibitors may be beneficial for treating acute lung injury. The important role of T-type calcium channel in the acute lung injury is encouraged to be further investigated.

scholarly journals Protective effects of ulinastatin and methylprednisolone against radiation-induced lung injury in mice

2016 ◽  
Vol 57 (5) ◽  
pp. 505-511 ◽  
Author(s):  
Yu Sun ◽  
Yu-Jun Du ◽  
Hui Zhao ◽  
Guo-Xing Zhang ◽  
Ni Sun ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Tissue ◽  
Transforming Growth Factor ◽  
Lavage Fluid ◽  
Protective Effects ◽  
Pathological Changes ◽  
Tnf Α ◽  
Methylprednisolone Treatment ◽  
Radiation Induced ◽  
Tgf Β1

Abstract The effectiveness of ulinastatin and methylprednisolone in treating pathological changes in mice with radiation-induced lung injury (RILI) was evaluated. Forty C57BL/6 female mice received whole-chest radiation (1.5 Gy/min for 12 min) and were randomly allocated into Group R (single radiation, n =  10), Group U (ulinastatin treatment, n =  10), Group M (methylprednisolone treatment, n =  10), or Group UM (ulinastatin and methylprednisolone treatment, n =  10). Another 10 untreated mice served as controls (Group C). Pathological changes in lung tissue, pulmonary interstitial area density (PIAD) and expression levels of transforming growth factor β1 (TGF-β1) and tumor necrosis factor α (TNF-α) in lung tissue, serum and bronchoalveolar lavage fluid were determined. Alleviation of pathological changes in lung tissue was observed in Groups U, M and UM. Treatment with ulinastatin, methylprednisolone or both effectively delayed the development of fibrosis at 12 weeks after radiation. Ulinastatin, methylprednisolone or both could alleviate the radiation-induced increase in the PIAD ( P  < 0.05 or P  < 0.01). Treatment with ulinastatin, methylprednisolone or both significantly reduced the expression of TNF-α, but not TGF-β1, at 9 weeks after radiation compared with Group R ( P  < 0.01). Ulinastatin and / or methylprednisolone effectively decreased the level of TNF-α in lung tissue after RILI and inhibited both the inflammatory response and the development of fibrosis.

The role of annexin A1 peptide in regulating PI3K/Akt signaling pathway to reduce lung injury after cardiopulmonary bypass in rats

Perfusion ◽  
2021 ◽  
pp. 026765912110521
Author(s):  
Yunzi He ◽  
Yuanjie Zhang ◽  
Hanhua Wu ◽  
Junli Luo ◽  
Chi Cheng ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bronchoalveolar Lavage Fluid ◽  
Oxygenation Index ◽  
Lavage Fluid ◽  
Akt Signaling ◽  
Annexin A1 ◽  
Akt Signaling Pathway ◽  
Group I ◽  
Tnf Α

Introduction Cardiopulmonary bypass (CPB) –induced lung ischemia-reperfusion (I/R) injury remains a large challenge in cardiac surgery; up to date, no effective treatment has been found. Annexin A1 (AnxA1) has an anti-inflammatory effect, and it has been proven to have a protective effect on CPB-induced lung injury. However, the specific mechanism of AnxA1 in CPB-induced lung injury is not well studied. Therefore, we established a CPB-induced lung injury model to explore the relevant mechanism of AnxA1 and try to find an effective treatment for lung protection. Methods Male rats were randomized into five groups ( n = 6, each): sham (S group), I/R exposure (I/R group), I/R + dimethyl sulfoxide (D group), I/R + Ac2-26 (AnxA1 peptide) (A group), and I/R + LY294002 (a PI3K specific inhibitor) (AL group). Arterial blood gas analysis and calculation of the oxygenation index, and respiratory index were performed. The morphological changes in lung tissues were observed under light and electron microscopes. TNF-α and IL-6 and total protein in lung bronchoalveolar lavage fluid were detected via enzyme-linked immunosorbent assay. The expressions of PI3K, Akt, and NF-κB (p65) as well as p-PI3K, p-Akt, p-NF-κB (p65), and AnxA1 were detected via western blotting. Results Compared with the I/R group, the A group showed the following: lower lung pathological damage score; decreased expression of IL-6 and total protein in the bronchoalveolar lavage fluid, and TNF-α in the lung; increased lung oxygenation index; and improved lung function. These imply the protective role of Ac2-26, and show that LY294002 inhibited the ameliorative preconditioning effect of Ac2-26. Conclusion This finding suggested that the AnxA1 peptide Ac2-26 decreased the inflammation reaction and CPB-induced lung injury in rats, the lung protective effects of AnxA1may be correlated with the activation of PI3K/Akt signaling pathway.

scholarly journals TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia

2012 ◽  
Vol 302 (5) ◽  
pp. L447-L454 ◽  
Author(s):  
Louis R. Standiford ◽  
Theodore J. Standiford ◽  
Michael J. Newstead ◽  
Xianying Zeng ◽  
Megan N. Ballinger ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bacterial Pneumonia ◽  
Lavage Fluid ◽  
Alveolar Epithelial Cells ◽  
Intratracheal Administration ◽  
Bacterial Colony ◽  
Gram Negative ◽  
Gm Csf

Toll-like receptors (TLRs) are required for protective host defense against bacterial pathogens. However, the role of TLRs in regulating lung injury during Gram-negative bacterial pneumonia has not been thoroughly investigated. In this study, experiments were performed to evaluate the role of TLR4 in pulmonary responses against Klebsiella pneumoniae (Kp). Compared with wild-type (WT) (Balb/c) mice, mice with defective TLR4 signaling (TLR4lps-d mice) had substantially higher lung bacterial colony-forming units after intratracheal challenge with Kp, which was associated with considerably greater lung permeability and lung cell death. Reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA and protein was noted in lungs and bronchoalveolar lavage fluid of TLR4 mutant mice postintratracheal Kp compared with WT mice, and primary alveolar epithelial cells (AEC) harvested from TLR4lps-d mice produced significantly less GM-CSF in vitro in response to heat-killed Kp compared with WT AEC. TLR4lps-d AEC underwent significantly more apoptosis in response to heat-killed Kp in vitro, and treatment with GM-CSF protected these cells from apoptosis in response to Kp. Finally, intratracheal administration of GM-CSF in TLR4lps-d mice significantly decreased albumin leak, lung cell apoptosis, and bacteremia in Kp-infected mice. Based on these observations, we conclude that TLR4 plays a protective role on lung epithelium during Gram-negative bacterial pneumonia, an effect that is partially mediated by GM-CSF.

3-methyadenine inhibits lipopolysaccharides-induced pulmonary inflammation at the early stage of silicosis via blocking NF-κB signaling pathway

2021 ◽  
pp. 074823372110394
Author(s):  
Yujing Zhang ◽  
Shuai Huang ◽  
Shiyi Tan ◽  
Mingke Chen ◽  
Shang Yang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Late Stage ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Early Stage ◽  
Pulmonary Inflammation ◽  
Mechanism Study ◽  
Silica Dust ◽  
Tnf Α

Occupational exposure to silica dust is related to pulmonary inflammation and silicosis. Lipopolysaccharides (LPSs) could aggravate apoptosis in alveolar macrophages (AMs) of human silicosis through autophagy, yet how the reduction of autophagy attenuated LPS-induced lung injury and the related mechanisms need to be investigated. In the study, we aim to understand the role of 3-methyladenine (3-MA), an inhibitor of autophagy, in LPS-mediated inflammatory responses and fibrosis. We collected AMs from observers/silicosis patients. The results showed that LPS induced NF-κB-related pulmonary inflammation in observers and silicosis patients, as confirmed by an increase in the expression of IL-1β, IL-6, TNF-α, and p65, which could be inhibited by 3-MA treatment. In mice models, at the early stage (7d) of silicosis, but not the late (28d) stage, blocking autophagy reversed the increased levels of IL-1β, IL-6, TNF-α, and p65 caused by LPS. Mechanism study revealed that LPS triggered the expression of LC3 II, p62, and cleaved caspase-3 at the early stage exposed to silica, which could be restored by 3-MA, while there was no difference in the expression of LAMP1 either at the early or late stage of silicosis in different groups. Similarly, 3-MA treatment did not prevent fibrosis characterized by destroyed alveoli, collagen deposition, and increased expression of α-SMA and Col-1 induced by LPS at the late stage of silicosis. The results suggested that 3-MA has a role in the protection of lung injury at the early stage of silicosis and provided an experimental basis for preventive strategies of pulmonary inflammation and silicosis.

scholarly journals Phospholipase C-ε signaling mediates endothelial cell inflammation and barrier disruption in acute lung injury

2016 ◽  
Vol 311 (2) ◽  
pp. L517-L524 ◽  
Author(s):  
Kaiser M. Bijli ◽  
Fabeha Fazal ◽  
Spencer A. Slavin ◽  
Antony Leonard ◽  
Valerie Grose ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Phospholipase C ◽  
Phorbol Esters ◽  
Critical Determinant ◽  
Monocyte Chemoattractant Protein 1 ◽  
Barrier Disruption ◽  
Proinflammatory Mediators ◽  
Tnf Α

Phospholipase C-ε (PLC-ε) is a unique PLC isoform that can be regulated by multiple signaling inputs from both Ras family GTPases and heterotrimeric G proteins and has primary sites of expression in the heart and lung. Whereas the role of PLC-ε in cardiac function and pathology has been documented, its relevance in acute lung injury (ALI) is unclear. We used PLC-ε−/− mice to address the role of PLC-ε in regulating lung vascular inflammation and injury in an aerosolized bacterial LPS inhalation mouse model of ALI. PLC-ε−/− mice showed a marked decrease in LPS-induced proinflammatory mediators (ICAM-1, VCAM-1, TNF-α, IL-1β, IL-6, macrophage inflammatory protein 2, keratinocyte-derived cytokine, monocyte chemoattractant protein 1, and granulocyte-macrophage colony-stimulating factor), lung neutrophil infiltration and microvascular leakage, and loss of VE-cadherin compared with PLC-ε+/+ mice. These data identify PLC-ε as a critical determinant of proinflammatory and leaky phenotype of the lung. To test the possibility that PLC-ε activity in endothelial cells (EC) could contribute to ALI, we determined its role in EC inflammation and barrier disruption. RNAi knockdown of PLC-ε inhibited NF-κB activity in response to diverse proinflammatory stimuli, thrombin, LPS, TNF-α, and the nonreceptor agonist phorbol 13-myristate 12-acetate (phorbol esters) in EC. Depletion of PLC-ε also inhibited thrombin-induced expression of NF-κB target gene, VCAM-1. Importantly, PLC-ε knockdown also protected against thrombin-induced EC barrier disruption by inhibiting the loss of VE-cadherin at adherens junctions and formation of actin stress fibers. These data identify PLC-ε as a novel regulator of EC inflammation and permeability and show a hitherto unknown role of PLC-ε in the pathogenesis of ALI.

scholarly journals Gut Lymph Purification in Rats With Acute Lung Injury Caused By Gut Ischemia Reperfusion Injury

2021 ◽  
Author(s):  
Can Jin ◽  
Shucheng Zhang ◽  
Linlin Wu ◽  
Bohan Li ◽  
Meimei Shi ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Reperfusion Injury ◽  
Lung Tissue ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mononuclear Phagocyte ◽  
Alveolar Epithelial Cells ◽  
Expression Level ◽  
Tissue Samples

Abstract Rationale: It is unclear whether removing the danger-associated molecular patterns (DAMPs) of gut lymph (GL) in the rats of gut ischemia-reperfusion injury (GIRI) model may reduce the distant organ lung injury.Objective: To determine whether oXiris gut lymph purification (GLP) may remove the DAMPs of GL in the rats’ model of acute lung injury (ALI) caused by GIRI.Methods: The experimental rats were divided into four groups: Sham group, GIRI group, GIRI + gut lymph drainage (GLD) group, and GIRI + GLP group. After successful modeling, the lung tissue samples of rats in each group were taken for hematoxylin-eosin (HE) staining and detection of expression levels of apoptotic indexes. The level of DAMPs was detected in blood and lymph. We observed its microstructure of type II alveolar epithelial cells (AECⅡ), and detected the expression level of apoptosis indexes.Measurements and Main Results: GIRI-induced destruction of alveolar structure, thickened alveolar walls, inflammatory cell infiltration emerged in the GIRI group, HMGB-1 and IL-6 levels significantly increased, and HSP70 and IL-10 levels reduced in lymph and serum. Compared with GIRI group, the lung tissue damage in GIRI + GLP group significantly improved, the expression level of HMGB-1 and IL-6 in the lymph and serum reduced, and HSP70 and IL-10 increased. The organelle structure of AECII in GIRI + GLP group was significantly improved compared with the GIRI group. Conclusions: oXiris GLP blocks the key link between DAMPs and mononuclear phagocyte system to inhibit inflammation and cell apoptosis, thereby reducing ALI induced by GIRI.

scholarly journals Effects of CX3CL1 inhibition on murine bleomycin-induced interstitial pneumonia

2020 ◽  
Vol 18 ◽  
pp. 205873922095990
Author(s):  
Soichi Yamada ◽  
Shion Miyoshi ◽  
Junko Nishio ◽  
Satoshi Mizutani ◽  
Zento Yamada ◽  
...  
Keyword(s):  
Interstitial Pneumonia ◽  
T Cell Activation ◽  
Lung Tissue ◽  
Cell Activation ◽  
Immunohistochemical Analysis ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Novel Therapy ◽  
Tissue Sections

Background: Treatment for interstitial pneumonia (IP) associated with collagen diseases has not been established. There is a need to elucidate the pathogenesis of IP and develop a novel therapy. We aimed to clarify the role of chemokine (C-X3-C motif) ligand 1 (CX3CL1, also known as fractalkine) in IP. Methods: Bleomycin (BLM) was intratracheally administered to C57BL/6 mice to induce IP. For treatment with control Ab or anti-CX3CL1 mAb, the mice were administered either Ab three times per week for 2 weeks from the day of BLM administration until euthanasia. Expressions of CX3CL1 and its unique receptor CX3CR1 in the lung tissue were examined by immunohistochemical analysis. Cellular infiltration and lung fibrosis were evaluated based on hematoxylin-eosin-staining and Sirius red staining of the lung tissue sections, respectively. Bronchoalveolar lavage fluid (BALF) cells were analyzed by flow cytometry. Results: CX3CL1 and CX3CR1 were strongly expressed in the lung tissue from mice with BLM-induced IP (BLM-IP). Treatment with anti-CX3CL1 mAb did not significantly alter inflammatory cell infiltration or fibrosis in the lung tissue. However, the number of M1-like macrophages in BALF was decreased and surface CD3 expression on T cells was increased by anti-CX3CL1 mAb treatment. Conclusions: Inhibition of CX3CL1 decreased inflammatory cells and may attenuate T cell activation in BALF. CX3CL1 inhibitor may have the potential to suppress the infiltration and activation of immune cells in IP.

scholarly journals A20: a master regulator of arthritis

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Yongyao Wu ◽  
Xiaomin He ◽  
Ning Huang ◽  
Jiayun Yu ◽  
Bin Shao
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Mouse Models ◽  
Inflammatory Arthritis ◽  
Molecular Mechanisms ◽  
Related Research ◽  
Inflammatory Protein ◽  
New Findings ◽  
Tnf Α

Abstract A20, also known as TNF-α-induced protein 3 (TNFAIP3), is an anti-inflammatory protein that plays an important part in both immune responses and cell death. Impaired A20 function is associated with several human inflammatory and autoimmune diseases. Although the role of A20 in mediating inflammation has been frequently discussed, its intrinsic link to arthritis awaits further explanation. Here, we review new findings that further demonstrate the molecular mechanisms through which A20 regulates inflammatory arthritis, and we discuss the regulation of A20 by many factors. We conclude by reviewing the latest A20-associated mouse models that have been applied in related research because they reflect the characteristics of arthritis, the study of which will hopefully cast new light on anti-arthritis treatments.

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