SP-A enhances viral clearance and inhibits inflammation after pulmonary adenoviral infection

1999 ◽  
Vol 277 (3) ◽  
pp. L580-L588 ◽  
Author(s):  
Kevin S. Harrod ◽  
Bruce C. Trapnell ◽  
Kazuhisa Otake ◽  
Thomas R. Korfhagen ◽  
Jeffrey A. Whitsett
Keyword(s):  
Host Defense ◽  
Lung Inflammation ◽  
Cell Injury ◽  
Recombinant Adenovirus ◽  
Protein A ◽  
Lavage Fluid ◽  
Viral Clearance ◽  
Polymorphonuclear Cells ◽  
Adenoviral Infection ◽  
Tnf Α

Surfactant protein A (SP-A) is a member of the collectin family of host defense molecules expressed primarily in the epithelial cells of the lung. To determine the role of SP-A in pulmonary adenoviral infection, SP-A-deficient (SP-A −/−) mice were intratracheally infected with a replication-deficient recombinant adenovirus, Av1Luc1. Lung inflammation was markedly increased in SP-A −/− compared with SP-A +/+ mice and was associated with increased hemorrhage and epithelial cell injury. Polymorphonuclear cells in bronchoalveolar lavage fluid (BALF) were increased in SP-A −/− mice after administration of adenovirus. Coadministration of adenovirus and purified human SP-A ameliorated adenoviral-induced lung inflammation in SP-A −/− mice. Concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were increased in BALF of SP-A −/− mice. Likewise, TNF-α, IL-6, macrophage inflammatory protein (MIP)-1α, monocyte chemotactic protein-1, and MIP-2 mRNAs were increased in lung homogenates from SP-A −/− mice 6 and 24 h after viral administration. Clearance of adenoviral DNA from the lung and uptake of fluorescent-labeled adenovirus by alveolar macrophages were decreased in SP-A −/− mice. SP-A enhances viral clearance and inhibits lung inflammation during pulmonary adenoviral infection, providing support for the importance of SP-A in antiviral host defense.

Adenoviral E3-14.7K protein in LPS-induced lung inflammation

2000 ◽  
Vol 278 (4) ◽  
pp. L631-L639 ◽  
Author(s):  
Kevin S. Harrod ◽  
Amber D. Mounday ◽  
Jeffrey A. Whitsett
Keyword(s):  
Transgenic Mice ◽  
Lung Inflammation ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Respiratory Epithelium ◽  
Wild Type ◽  
Intracellular Staining ◽  
Intratracheal Administration ◽  
Tnf Α

The adenoviral E3-14.7K protein is a cytoplasmic protein synthesized after adenoviral infection. To assess the contribution of E3-14.7K-sensitive pathways in the modulation of inflammation by the respiratory epithelium, inflammatory responses to intratracheal lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α were assessed in transgenic mice bearing the adenoviral E3-14.7K gene under the direction of the surfactant protein (SP) C promoter. When E3-14.7K transgenic mice were administered LPS intratracheally, lung inflammation as indicated by macrophage and neutrophil accumulation in bronchoalveolar lavage fluid was decreased compared with wild-type control mice. Lung inflammation and epithelial cell injury were decreased in E3-14.7K mice 24 and 48 h after LPS administration. Intracellular staining for surfactant proprotein (proSP) B, proSP-C, and SP-B was decreased and extracellular staining was markedly increased in wild-type mice after LPS administration, consistent with LPS-induced lung injury. In contrast, intense intracellular staining of proSP-B, proSP-C, and SP-B persisted in type II cells of E3-14.7K mice, whereas extracellular staining of proSP-B and proSP-C was absent. Inhibitory effects of intratracheal LPS on SP-C mRNA were ameliorated by expression of the E3-14.7Kgene. Similar to the response to LPS, lung inflammation after intratracheal administration of TNF-α was decreased in E3-14.7K transgenic mice. Levels of TNF-α after LPS administration were similar in wild-type and E3-14.7K-bearing mice. Cell-selective expression of E3-14.7K in the respiratory epithelium inhibited LPS- and TNF-α-mediated lung inflammation, demonstrating the critical role of respiratory epithelial cells in LPS- and TNF-α-induced lung inflammation.

Time-response relationship of nano and micro particle induced lung inflammation. Quartz as reference compound

2010 ◽  
Vol 29 (11) ◽  
pp. 915-933 ◽  
Author(s):  
Martin Roursgaard ◽  
Steen S Poulsen ◽  
Lars K Poulsen ◽  
Maria Hammer ◽  
Keld A Jensen ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Acute Inflammation ◽  
Lavage Fluid ◽  
Milling Process ◽  
Time Response ◽  
Substantial Part ◽  
Screening Methods ◽  
Inflammatory Protein ◽  
Tnf Α ◽  
Two Samples

An increasing number of engineered particles, including nanoparticles, are being manufactured, increasing the need for simple low-dose toxicological screening methods. This study aimed to investigate the kinetics of biomarkers related to acute and sub-chronic particle-induced lung inflammation of quartz. Mice were intratracheal instilled with 50 µg of microsized or nanosized quartz. Acute inflammation was assessed 1, 2, 4, 8, 16 or 48 hours post exposure, whereas sub-chronic inflammation was investigated 3 months after exposure. Markers of acute inflammation in the bronchoalveolar lavage fluid (BALF) were neutrophils (PMN), tumor necrosis factor-alfa (TNF-α), interleukin (IL)-1β, macrophage inflammatory protein-2 (MIP-2), keratinocyte derived chemokine (KC) and total protein, which were all close to maximum 16 hours post instillation. No major differences were seen in the time-response profiles of nano- and micro-sized particles. The potency of the two samples cannot be compared; during the milling process, a substantial part of the quartz was converted to amorphous silica and contaminated with corundum. For screening, BALF PMN, either TNF-α or IL-1β at 16 hours post instillation may be useful. At 3 months post instillation, KC, PMN and macrophages were elevated. Histology showed no interstitial inflammation three months post instillation. For screening of sub-chronic effects, KC, PMN, macrophages and histopathology is considered sufficient.

Regulatory Effects of Andrographolide on Lung Tissue Inflammation and Th17/Treg in Rats with Chronic Obstructive Pulmonary Disease Induced by Smoking and Lipopolysaccharide

2021 ◽  
Vol 11 (3) ◽  
pp. 513-519
Author(s):  
Hong Li ◽  
Shuang Song ◽  
Zhibin Kong ◽  
Zhen Zhu ◽  
Yi Liu ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Blood Cells ◽  
Lung Inflammation ◽  
White Blood Cells ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Protein Levels ◽  
Tnf Α ◽  
Monocytes And Macrophages

The pathogenesis of Chronic obstructive pulmonary disease (COPD) is complex, and lung tissue inflammation and Th17/Treg imbalance are the key factors causing lung dysfunction. We constructed a rat COPD model induced by smoking and lipopolysaccharide to explore andrographolide’s regulation on lung inflammation and Th17/Treg in COPD rats. By contrast, the study found that normal rats, COPD rats forced expiratory volume of 0.3 seconds (FEV0.3), FEV0.3/forced vital capacity (FVC), and peak expiratory flow (PEF) levels decreased. In addition, the levels of IL-8, TNF-α, IL-17, and IL-6 in alveolar lavage fluid increased, and the level of IL-10 decreased. Concurrently, the total number of white blood cells, monocytes and macrophages, neutrophils, and lymphocytes increased. Meanwhile, the contents of CD25, CD4, and Foxp3 in lung tissue all increased, and the protein levels of HMGB1, TLR4, and p65 increased. After treatment with andrographolide, the levels of FEV0.3, FEV0.3/FVC, and PEF increased, proving the increase was positively correlated with the concentration of andrographolide. The levels of IL-8, TNF-α, IL-17, and IL-6 in rat alveolar lavage fluid decreased, and the level of IL-10 sequentially. The total number of white blood cells, the number of monocytes and macrophages, the number of lymphocytes, and the neutral Granulocytes decreased significantly. And the contents of CD25, CD4, and Foxp3 in lung tissue significantly decreased, and the protein levels of HMGB1, TLR4, and p65 significantly decreased. The above results indicate that andrographolide might be a potential COPD treatment approach. Andrographolide improves the lung function of rats with COPD, reduces lung inflammation, regulates Th17/Treg balance, and its mechanism may be related to HMGB1/TLR4/NF-кB signaling.

scholarly journals Agmatine Protects against Zymosan-Induced Acute Lung Injury in Mice by Inhibiting NF-κB-Mediated Inflammatory Response

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Xuanfei Li ◽  
Zheng Liu ◽  
He Jin ◽  
Xia Fan ◽  
Xue Yang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Weight Ratio ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Myeloperoxidase Activity ◽  
Beneficial Effects ◽  
Hypoxic Ischemia ◽  
Tnf Α

Acute lung injury (ALI) is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Agmatine, a cationic polyamine formed by decarboxylation of L-arginine, is an endogenous neuromodulator that plays protective roles in diverse central nervous system (CNS) disorders. Consistent with its neuromodulatory and neuroprotective properties, agmatine has been reported to have beneficial effects on depression, anxiety, hypoxic ischemia, Parkinson’s disease, and gastric disorder. In this study, we tested the effect of agmatine on the lung inflammation induced by Zymosan (ZYM) challenge in mice. We found that agmatine treatment relieved ZYM-induced acute lung injury, as evidenced by the reduced histological scores, wet/dry weight ratio, and myeloperoxidase activity in the lung tissue. This was accompanied by reduced levels of TNF-α, IL-1β, and IL-6 in lung and bronchoalveolar lavage fluid and decreased iNOS expression in lung. Furthermore, agmatine inhibited the phosphorylation and degradation of IκB and subsequently blocked the activation of nuclear factor (NF)-κB induced by Zymosan. Taken together, our results showed that agmatine treatment inhibited NF-κB signaling in lungs and protected mice against ALI induced by Zymosan, suggesting agmatine may be a potential safe and effective approach for the treatment of ALI.

Role of PAR2 in murine pulmonary pseudomonal infection

2008 ◽  
Vol 294 (2) ◽  
pp. L368-L377 ◽  
Author(s):  
Theo J. Moraes ◽  
Raiza Martin ◽  
Jonathan D. Plumb ◽  
Eric Vachon ◽  
Cheryl M. Cameron ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Lavage Fluid ◽  
Wild Type ◽  
Protease Activated Receptors ◽  
Tnf Α ◽  
Pulmonary Inflammatory Response ◽  
Ifn Γ ◽  
Genetic Deletion

Proteinases can influence lung inflammation by various mechanisms, including via cleavage and activation of protease-activated receptors (PAR) such as PAR2. In addition, proteinases such as neutrophil and/or Pseudomonas-derived elastase can disarm PAR2 resulting in loss of PAR2 signaling. Currently, the role of PAR2 in host defense against bacterial infection is not known. Using a murine model of acute Pseudomonas aeruginosa pneumonia, we examined differences in the pulmonary inflammatory response between wild-type and PAR2−/−mice. Compared with wild-type mice, PAR2−/−mice displayed more severe lung inflammation and injury in response to P. aeruginosa infection as indicated by higher bronchoalveolar lavage fluid neutrophil numbers, protein concentration, and TNF-α levels. By contrast, IFN-γ levels were markedly reduced in PAR2−/−compared with wild-type mice. Importantly, clearance of P. aeruginosa was diminished in PAR2−/−mice. In vitro testing revealed that PAR2−/−neutrophils killed significantly less bacteria than wild-type murine neutrophils. Further, both neutrophils and macrophages from PAR2−/−mice displayed significantly reduced phagocytic efficiency compared with wild-type phagocytes. Stimulation of PAR2 on macrophages using a PAR2-activating peptide resulted in enhanced phagocytosis directly implicating PAR2 signaling in the phagocytic process. We conclude that genetic deletion of PAR2 is associated with decreased clearance of P. aeruginosa. Our data suggest that a deficiency in IFN-γ production and impaired bacterial phagocytosis are two potential mechanisms responsible for this defect.

scholarly journals Nrf2 Lowers the Risk of Lung Injury via Modulating the Airway Innate Immune Response Induced by Diesel Exhaust in Mice

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 443
Author(s):  
Ying-Ji Li ◽  
Takako Shimizu ◽  
Yusuke Shinkai ◽  
Tomomi Ihara ◽  
Masao Sugamata ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Lung Tissue ◽  
Diesel Exhaust ◽  
Cell Injury ◽  
Lamellar Body ◽  
Lavage Fluid ◽  
Innate Immune ◽  
Alveolar Type ◽  
Tnf Α

In the present study, we investigated the role of Nrf2 in airway immune responses induced by diesel exhaust (DE) inhalation in mice. C57BL/6J Nrf2+/+ and Nrf2−/− mice were exposed to DE or clean air for 8 h/day and 6 days/week for 4 weeks. After DE exposure, the number of neutrophils and macrophage inflammatory protein (MIP)-2 level in bronchoalveolar lavage fluid (BALF) and interleukin (IL)-17 level in the lung tissue increased in Nrf2−/− mice compared with Nrf2+/+ mice; however, the lack of an increase in the level of tumor necrosis factor (TNF)-α in the lung tissue in Nrf2+/+ mice and mild suppression of the level of TNF-α in Nrf2−/− mice were observed; the level of granulocyte macrophage colony-stimulating factor (GM-CSF) in the lung tissue decreased in Nrf2−/− mice than in Nrf2+/+ mice; the number of DE particle-laden alveolar macrophages in BALF were larger in Nrf2−/− mice than in Nrf2+/+ mice. The results of electron microscope observations showed alveolar type II cell injury and degeneration of the lamellar body after DE exposure in Nrf2−/− mice. Antioxidant enzyme NAD(P)H quinone dehydrogenase (NQO)1 mRNA expression level was higher in Nrf2+/+ mice than in Nrf2−/− mice after DE exposure. Our results suggested that Nrf2 reduces the risk of pulmonary disease via modulating the airway innate immune response caused by DE in mice.

Clara cell secretory protein decreases lung inflammation after acute virus infection

1998 ◽  
Vol 275 (5) ◽  
pp. L924-L930 ◽  
Author(s):  
Kevin S. Harrod ◽  
Amber D. Mounday ◽  
Barry R. Stripp ◽  
Jeffrey A. Whitsett
Keyword(s):  
Viral Infection ◽  
Lung Inflammation ◽  
Cell Injury ◽  
Pulmonary Inflammation ◽  
Secretory Protein ◽  
Clara Cell ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Adenoviral Infection ◽  
Clara Cell Secretory Protein

Clara cell secretory protein (CCSP) is an abundant 10-kDa polypeptide synthesized and secreted primarily by nonciliated bronchiolar epithelial cells in the mammalian lung. To determine the potential role of CCSP in pulmonary inflammation after acute viral infection, CCSP gene-targeted {CCSP-deficient [CCSP(−/−)]} mice were exposed to a recombinant E1- and E3-deficient adenoviral vector, Av1Luc1, intratracheally. Lung inflammation was markedly increased in CCSP(−/−) mice compared with wild-type control mice and was associated with an increased number of polymorphonuclear cell infiltrates and epithelial cell injury in both conducting airways and alveolar regions. Histological evidence of pulmonary inflammation in CCSP(−/−) mice was associated with increased production of cytokine (interleukin-1β and -6 and tumor necrosis factor-α) mRNA and protein, as well as chemokine (macrophage inflammatory protein-1α and -2 and monocyte chemoattractant protein-1) mRNA expression within the lung in response to adenoviral infection. Adenoviral-mediated gene transfer was decreased in CCSP(−/−) mice relative to wild-type mice as measured by luciferase enzyme activity in lung homogenates. The present study suggests that CCSP is involved in modulating lung inflammation during viral infection and supports a role for CCSP in lung host defense.

TNF-α Suppresses Autophagic Flux in Acinar Cells in IgG4-Related Sialadenitis

2019 ◽  
Vol 98 (12) ◽  
pp. 1386-1396 ◽  
Author(s):  
X. Hong ◽  
S.N. Min ◽  
Y.Y. Zhang ◽  
Y.T. Lin ◽  
F. Wang ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Cell Injury ◽  
Ex Vivo ◽  
Secretory Granules ◽  
Acinar Cells ◽  
Autophagic Flux ◽  
C6 Cells ◽  
Tnf Α ◽  
Α Level

IgG4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic fibroinflammatory disease that affects salivary glands and leads to hyposalivation. Tumor necrosis factor–α (TNF-α) is a critical proinflammatory cytokine involved in several salivary gland disorders, but its role and mechanism regarding acinar cell injury in IgG4-RS are unknown. Here, we found that TNF-α level was significantly increased in serum and submandibular gland (SMG) of patients and that serum TNF-α level was negatively correlated with saliva flow rate. Ultrastructural observations of IgG4-RS SMGs revealed accumulation of large autophagic vacuoles, as well as dense fibrous bundles, decreased secretory granules, widened intercellular spaces, swollen mitochondria, and expanded endoplasmic reticulum. Expression levels of LC3 and p62 were both increased in patients’ SMGs. TNF-α treatment led to elevated levels of LC3II and p62 in both SMG-C6 cells and cultured human SMG tissues but did not further increase their levels when combined with bafilomycin A1 treatment. Moreover, transfection of Ad-mCherry-GFP-LC3B in SMG-C6 cells confirmed the suppression of autophagic flux after TNF-α treatment. Immunofluorescence imaging revealed that costaining of LC3 and the lysosomal marker LAMP2 was significantly decreased in patients, TNF-α–treated SMG-C6 cells, and cultured human SMGs, indicating a reduction in autophagosome-lysosome fusion. Furthermore, the ratio of pro/mature cathepsin D was elevated in vivo, ex vivo, and in vitro. TNF-α also appeared to induce abnormal acidification of lysosomes in acinar cells, as assessed by lysosomal pH and LysoTracker DND-26 fluorescence intensity. In addition, TNF-α treatment induced transcription factor EB (TFEB) redistribution in SMG-C6 cells, which was consistent with the changes observed in IgG4-RS patients. TNF-α increased the phosphorylation of extracellular signal–regulated kinase (ERK) 1/2, and inhibition of ERK1/2 by U0126 reversed TNF-α–induced TFEB redistribution, lysosomal dysfunction, and autophagic flux suppression. These findings suggest that TNF-α is a key cytokine related to acinar cell injury in IgG4-RS through ERK1/2-mediated autophagic flux suppression.

scholarly journals Cangrelor ameliorates CLP-induced pulmonary injury in sepsis by inhibiting GPR17

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Qiancheng Luo ◽  
Rui Liu ◽  
Kaili Qu ◽  
Guorong Liu ◽  
Min Hang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Lavage Fluid ◽  
Surface Expression ◽  
Pulmonary Injury ◽  
Protective Mechanisms ◽  
Tnf Α ◽  
Anti Platelet Drug ◽  
G Protein Coupled ◽  
Very High ◽  
Masson Staining

Abstract Background Sepsis is a common complication of severe wound injury and infection, with a very high mortality rate. The P2Y12 receptor inhibitor, cangrelor, is an antagonist anti-platelet drug. Methods In our study, we investigated the protective mechanisms of cangrelor in CLP-induced pulmonary injury in sepsis, using C57BL/6 mouse models. Results TdT-mediated dUTP Nick-End Labeling (TUNEL) and Masson staining showed that apoptosis and fibrosis in lungs were alleviated by cangrelor treatment. Cangrelor significantly promoted surface expression of CD40L on platelets and inhibited CLP-induced neutrophils in Bronchoalveolar lavage fluid (BALF) (p < 0.001). We also found that cangrelor decreased the inflammatory response in the CLP mouse model and inhibited the expression of inflammatory cytokines, IL-1β (p  < 0.01), IL-6 (p < 0.05), and TNF-α (p < 0.001). Western blotting and RT-PCR showed that cangrelor inhibited the increased levels of G-protein-coupled receptor 17 (GPR17) induced by CLP (p < 0.001). Conclusion Our study indicated that cangrelor repressed the levels of GPR17, followed by a decrease in the inflammatory response and a rise of neutrophils in BALF, potentially reversing CLP-mediated pulmonary injury during sepsis.

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