Functional alterations of alveolar macrophages subjected to smoke exposure and antioxidant lazaroids

1999 ◽  
Vol 15 (5) ◽  
pp. 464-469 ◽  
Author(s):  
Shengjun Wang ◽  
R. Clark Lantz ◽  
Mary W. Vermeulen ◽  
Guan Jie Chen ◽  
Veronica Breceda ◽  
...  
Keyword(s):  
Lung Injury ◽  
Alveolar Macrophages ◽  
Cell Injury ◽  
Mrna Level ◽  
Smoke Exposure ◽  
Acute Injury ◽  
Smoke Control ◽  
Protein Levels ◽  
Tnf Α

Acute inhalation of diesel fuel-polycarbonate plastic (DFPP) smoke causes severe lung injury, leading to acute respiratory distress syndrome (ARDS) and death. It has been reported that the initiation of acute lung injury is associated with the activation of pulmonary alveolar macrophages (PAM). To further explore the pathogenesis, alveolar macrophages (AM) of New Zealand rabbits ventilated and exposed to a 60 tidal volume of DFPP smoke in vivo were recovered at 1 h post-smoke. Smoke exposure induced significant increases in both mRNA and protein levels for PAM tumor necrosis factor-α (TNF-α), when compared to smoke control. Smoke also induced a biphasic response (inhibited at 2 h, enhanced at 24 h after cell isolation) in the production of superoxide (O2−) by PAM. However, aerosolized lazaroid, U75412E (1.6 mg/kg body weight), significantly attenuated smoke-induced expression in AM TNF-α at the protein level but not at the mRNA level, and smoke-induced changes in AM production of O2−. This study suggests that highly expressing AM TNF-α following smoke may be a key contributor to the cascade that establishes an acute injury process and exacerbates oxidant-derived cell injury. Whereas, the lazaroid may ameliorate smoke-induced lung injury by attenuating AM TNF-α release, in addition to its primary antioxidative mechanism.

scholarly journals Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS-induced acute lung injury

2021 ◽  
Author(s):  
Yuanxu Jiang ◽  
Mingzhu Xia ◽  
Jing Xu ◽  
Qiang Huang ◽  
Zhongliang Dai ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Sodium Channel ◽  
Pulmonary Edema ◽  
Cell Injury ◽  
A549 Cells ◽  
Alveolar Epithelial ◽  
Phosphorylated Akt ◽  
Epithelial Sodium Channel Enac

AbstractDexmedetomidine (Dex), a highly selective α2-adrenergic receptor (α2AR) agonist, has an anti-inflammatory property and can alleviate pulmonary edema in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the mechanism is still unclear. In this study, we attempted to investigate the effect of Dex on alveolar epithelial sodium channel (ENaC) in the modulation of alveolar fluid clearance (AFC) and the underlying mechanism. Lipopolysaccharide (LPS) was used to induce acute lung injury (ALI) in rats and alveolar epithelial cell injury in A549 cells. In vivo, Dex markedly reduced pulmonary edema induced by LPS through promoting AFC, prevented LPS-induced downregulation of α-, β-, and γ-ENaC expression, attenuated inflammatory cell infiltration in lung tissue, reduced the concentrations of TNF-α, IL-1β, and IL-6, and increased concentrations of IL-10 in bronchoalveolar lavage fluid (BALF). In A549 cells stimulated with LPS, Dex attenuated LPS-mediated cell injury and the downregulation of α-, β-, and γ-ENaC expression. However, all of these effects were blocked by the PI3K inhibitor LY294002, suggesting that the protective role of Dex is PI3K-dependent. Additionally, Dex increased the expression of phosphorylated Akt and reduced the expression of Nedd4-2, while LY294002 reversed the effect of Dex in vivo and in vitro. Furthermore, insulin-like growth factor (IGF)-1, a PI3K agonists, promoted the expression of phosphorylated Akt and reduced the expression of Nedd4-2 in LPS-stimulated A549 cells, indicating that Dex worked through PI3K, and Akt and Nedd4-2 are downstream of PI3K. In conclusion, Dex alleviates pulmonary edema by suppressing inflammatory response in LPS-induced ALI, and the mechanism is partly related to the upregulation of ENaC expression via the PI3K/Akt/Nedd4-2 signaling pathway.

RESPIRATORY SYNCYTIAL VIRUS LUNG INFECTION IN INFANTS: IMMUNOREGULATORY ROLE OF INFECTED ALVEOLAR MACROPHAGES

PEDIATRICS ◽  
1995 ◽  
Vol 96 (2) ◽  
pp. 391-391
Author(s):  
Leon S. Greos
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Lung Infection ◽  
Local Immune Response ◽  
Rsv Infection ◽  
Syncytial Virus

Alveolar macrophages are infected by RSV in vivo and coexpress potent immunomodulatory molecules that potentially regulate local immune response or lung injury caused by RSV infection.

Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury

2013 ◽  
Vol 304 (4) ◽  
pp. L221-L229 ◽  
Author(s):  
Zirak Hasan ◽  
Milladur Rahman ◽  
Karzan Palani ◽  
Ingvar Syk ◽  
Bengt Jeppsson ◽  
...  
Keyword(s):  
Lung Injury ◽  
Alveolar Macrophages ◽  
Neutrophil Infiltration ◽  
Abdominal Sepsis ◽  
Neutrophil Recruitment ◽  
Chemokine Production ◽  
Tnf Α ◽  
Cxc Chemokine ◽  
Geranylgeranyl Transferase

Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal sepsis. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets. Gene expression of CXC chemokines, tumor necrosis factor-α (TNF-α), and CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils, edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably, GGTI-2133 abolished CLP-induced formation of CXC chemokines, TNF-α, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl transferase inhibition had no effect on sepsis-induced platelet shedding of CD40L. In addition, inhibition of geranylgeranyl transferase markedly decreased CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl transferase is an important regulator of CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl transferase might be a potent way to attenuate acute lung injury in abdominal sepsis.

Evidence for reprogramming of monocytes into reparative alveolar macrophages in vivo by targeting PDE4b

2021 ◽  
Author(s):  
Ian Rochford ◽  
Jagdish Chandra Joshi ◽  
Rayees Sheikh ◽  
Mumtaz Anwar ◽  
Md Zahid Akhter ◽  
...  
Keyword(s):  
Lung Injury ◽  
Alveolar Macrophages ◽  
Lung Edema ◽  
Rna Seq ◽  
Activation Of Transcription ◽  
The Impact ◽  
Camp Levels ◽  
Phosphodiesterase 4B ◽  
Lung Vascular Permeability

Increased lung vascular permeability and neutrophilic inflammation are hallmarks of acute lung injury. Alveolar macrophages (AMϕ), the predominant sentinel cell type in the airspace, die in massive numbers while fending off pathogens. Recent studies indicate that the AMϕ pool is replenished by airspace-recruited monocytes, but the mechanisms instructing the conversion of recruited monocytes into reparative AMϕ remain elusive. Cyclic AMP (cAMP) is a vascular barrier protective and immunosuppressive second messenger in the lung. Here, we subjected mice expressing GFP under the control of the Lysozyme-M promoter (LysM-GFP mice) to the LPS model of rapidly resolving lung injury to address the impact of mechanisms determining cAMP levels in AMϕ and regulation of mobilization of the reparative AMϕ-pool. RNA-seq analysis of flow-sorted Mϕ identified phosphodiesterase 4b (PDE4b) as the top LPS-responsive cAMP-regulating gene. We observed that PDE4b expression markedly increased at the time of peak injury (4 h) and then decreased to below the basal level during the resolution phase (24 h). Activation of transcription factor NFATc2 was required for transcription of PDE4b in Mϕ. Inhibition of PDE4 activity at the time of peak injury, using i.t. rolipram, increased cAMP levels, augmented the reparative AMϕ pool, and resolved lung injury. This response was not seen following conditional depletion of monocytes, thus establishing airspace-recruited PDE4b-sensitive monocytes as the source of reparative AMϕ. Interestingly, adoptive transfer of rolipram-educated AMϕ into injured mice resolved lung edema. We propose suppression of PDE4b as an effective approach to promote reparative AMϕ generation from monocytes for lung repair.

Shen-Fu Attenuates Endotoxin-Induced Acute Lung Injury in Rats

2006 ◽  
Vol 34 (04) ◽  
pp. 613-621 ◽  
Author(s):  
Yanning Qian ◽  
Jie Sun ◽  
Zhongyun Wang ◽  
Jianjun Yang
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Inflammation ◽  
Weight Ratio ◽  
Dry Weight ◽  
Nf Kappa B ◽  
Lung Weight ◽  
Tnf Α ◽  
Male Wistar Rats

Sepsis is associated with the highest risk of progression to acute lung injury or acute respiratory distress syndrome. Shen-Fu has been advocated to treat many severely ill patients. Our study was designed to investigate the effect of Shen-Fu on endotoxin-induced acute lung injury in vivo. Adult male Wistar rats were randomly divided into 6 groups: controls; those challenged with endotoxin (5 mg/kg) and treated with saline; those challenged with endotoxin (5 mg/kg) and treated with Shen-Fu (1 mg/kg); those challenged with endotoxin (5 mg/kg) and treated with Shen-Fu (10 mg/kg); increase challenged with endotoxin (5 mg/kg) and treated with Shen-Fu (100 mg/kg); saline injected and treated with Shen-Fu (100 mg/kg). TNF-α, IL-6, and NF-kappa B were investigated in the lung two hours later. Myeloperoxidase (MPO) activity and wet/dry weight ratio were investigated six hours later. Intravenous administration of endotoxin provoked significant lung injury, which was characterized by increment increase of MPO activity and wet/dry lung weight ratio, and TNF-α and IL-6 expression and NF-kappa B activation. Shen-Fu (10,100 mg/kg) decreased MPO activity and wet/dry weight ratio and inhibited TNF-α and IL-6 production, endotoxin-induced NF-kappa B activation. Our results indicated that Shen-Fu at a dose of higher than 10 mg/kg inhibited endotoxin-induced pulmonary inflammation in vivo.

Impaired functional activity of alveolar macrophages from GM-CSF-deficient mice

2001 ◽  
Vol 281 (5) ◽  
pp. L1210-L1218 ◽  
Author(s):  
Robert Paine ◽  
Susan B. Morris ◽  
Hong Jin ◽  
Steven E. Wilcoxen ◽  
Susan M. Phare ◽  
...  
Keyword(s):  
Host Defense ◽  
Alveolar Macrophages ◽  
Phagocytic Activity ◽  
Wild Type ◽  
Specific Expression ◽  
Gm Csf ◽  
Functional Capabilities ◽  
Tnf Α

We hypothesized that pulmonary granulocyte-macrophage colony-stimulating factor (GM-CSF) is critically involved in determining the functional capabilities of alveolar macrophages (AM) for host defense. To test this hypothesis, cells were collected by lung lavage from GM-CSF mutant mice [GM(−/−)] and C57BL/6 wild-type mice. GM(−/−) mice yielded almost 4-fold more AM than wild-type mice. The percentage of cells positive for the β2-integrins CD11a and CD11c was reduced significantly in GM(−/−) AM compared with wild-type cells, whereas expression of CD11b was similar in the two groups. The phagocytic activity of GM(−/−) AM for FITC-labeled microspheres was impaired significantly compared with that of wild-type AM both in vitro and in vivo (after intratracheal inoculation with FITC-labeled beads). Stimulated secretion of tumor necrosis factor-α (TNF-α) and leukotrienes by AM from the GM(−/−) mice was greatly reduced compared with wild-type AM, whereas secretion of monocyte chemoattractant protein-1 was increased. Transgenic expression of GM-CSF exclusively in the lungs of GM(−/−) mice resulted in AM with normal or supranormal expression of CD11a and CD11c, phagocytic activity, and TNF-α secretion. Thus, in the absence of GM-CSF, AM functional capabilities for host defense were significantly impaired but were restored by lung-specific expression of GM-CSF.

TNF-α causes reversible in vivo systemic vascular barrier dysfunction via NO-dependent and -independent mechanisms

1997 ◽  
Vol 273 (6) ◽  
pp. H2565-H2574 ◽  
Author(s):  
Neil K. Worrall ◽  
Kathy Chang ◽  
Wanda S. Lejeune ◽  
Thomas P. Misko ◽  
Patrick M. Sullivan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lung Injury ◽  
Water Content ◽  
Selective Inhibition ◽  
No Production ◽  
Barrier Dysfunction ◽  
Barrier Integrity ◽  
Tnf Α ◽  
Severe Lung

Tumor necrosis factor (TNF-α) and nitric oxide (NO) are important vasoactive mediators of septic shock. This study used a well-characterized quantitative permeation method to examine the effect of TNF-α and NO on systemic vascular barrier function in vivo, without confounding endotoxemia, hypotension, or organ damage. Our results showed 1) TNF-α reversibly increased albumin permeation in the systemic vasculature (e.g., lung, liver, brain, etc.); 2) TNF-α did not affect hemodynamics or blood flow or cause significant tissue injury; 3) pulmonary vascular barrier dysfunction was associated with increased lung water content and impaired oxygenation; 4) TNF-α caused inducible nitric oxide synthase (iNOS) mRNA expression in the lung and increased in vivo NO production; 5) selective inhibition of iNOS with aminoguanidine prevented TNF-α-induced lung and liver vascular barrier dysfunction; 6) aminoguanidine prevented increased tissue water content in TNF-α-treated lungs and improved oxygenation; and 7) nonselective inhibition of NOS with N G-monomethly-l-arginine increased vascular permeation in control lungs and caused severe lung injury in TNF-α-treated animals. We conclude that 1) TNF-α reversibly impairs vascular barrier integrity through NO-dependent and -independent mechanisms; 2) nonselective NOS inhibition increased vascular barrier dysfunction and caused severe lung injury, whereas selective inhibition of iNOS prevented impaired endothelial barrier integrity and pulmonary dysfunction; and 3) selective inhibition of iNOS may be beneficial in treating increased vascular permeability that complicates endotoxemia and cytokine immunotherapy.

Enhancement of the endotoxin recognition pathway by ventilation with a large tidal volume in rabbits

2004 ◽  
Vol 286 (6) ◽  
pp. L1114-L1121 ◽  
Author(s):  
Kiyoshi Moriyama ◽  
Akitoshi Ishizaka ◽  
Morio Nakamura ◽  
Hiroshi Kubo ◽  
Toru Kotani ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tidal Volume ◽  
Mechanical Stress ◽  
Clinical Outcomes ◽  
Alveolar Macrophages ◽  
Fold Increase ◽  
Large Tidal Volume ◽  
Tnf Α ◽  
Cd14 Mrna

Ventilation with a small tidal volume (Vt) is associated with better clinical outcomes than with a large Vt, particularly in critical settings, including acute lung injury. To determine whether Vt influences the lipopolysaccaharide (LPS) recognition pathway, we studied CD14 expression in rabbit lungs and the release of TNF-α by cultured alveolar macrophages after 240 min of ventilation with a large (20 ml/kg) vs. a small (5 ml/kg) Vt. We also applied small or large Vt to lungs instilled with 50 μg/kg of LPS. The alveolar macrophages collected after large Vt ventilation revealed a 20-fold increase in LPS-induced TNF-α release compared with those collected after small Vt ventilation, whereas TNF-α was undetectable without LPS stimulation. In animals ventilated with a large Vt, the expression of CD14 mRNA in whole lung homogenates and the expression of CD14 protein on alveolar macrophages, assessed by immunohistochemistry, were both significantly increased in the absence of LPS stimulation. A large Vt applied to LPS-instilled lungs increased the pulmonary albumin permeability and TNF-α release into the plasma. These results suggest that mechanical stress caused by a large Vt sensitizes the lungs to endotoxin, a phenomenon that may occur partially via the upregulation of CD14.

scholarly journals Suppressive Effects of GSS on Lipopolysaccharide-Induced Endothelial Cell Injury and ALI via TNF-α and IL-6

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Lei Yi ◽  
Zengding Zhou ◽  
Yijuan Zheng ◽  
Mengling Chang ◽  
Xiaoqin Huang ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Injury ◽  
Inflammatory Mediator ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Promising Candidate ◽  
Neuroprotective Effects ◽  
Endothelial Cell Injury ◽  
Tnf Α

Background. Under septic conditions, LPS induced lung vascular endothelial cell (EC) injury, and the release of inflammatory mediator launches and aggravates acute lung injury (ALI). There are no effective therapeutic options for ALI. Genistein-3′-sodium sulfonate (GSS) is a derivative of native soy isoflavone, which exhibits neuroprotective effects via its antiapoptosis property. However, whether GSS protect against sepsis-induced EC injury and release of inflammatory mediators has not been determined. In this study, we found that GSS not only downregulated the levels of TNF-α and IL-6 in the lung and serum of mice in vivo but also inhibited the expression and secretion of TNF-α and IL-6 in ECs. Importantly, we also found that GSS blocked LPS-induced TNF-α and IL-6 expression in ECs via the Myd88/NF-κB signaling pathway. Taken together, our results demonstrated that GSS might be a promising candidate for sepsis-induced ALI via its regulating effects on inflammatory response in lung ECs.

IFN-γ and TNF-α decrease serotonin transporter function and expression in Caco2 cells

2007 ◽  
Vol 292 (3) ◽  
pp. G779-G784 ◽  
Author(s):  
Kevin F. Foley ◽  
Cristen Pantano ◽  
Allison Ciolino ◽  
Gary M. Mawe
Keyword(s):  
Ulcerative Colitis ◽  
Irritable Bowel Syndrome ◽  
Conditioned Medium ◽  
Human Lymphocytes ◽  
Protein Levels ◽  
Tnf Α ◽  
Ifn Γ ◽  
5 Ht Uptake ◽  
Irritable Bowel

Recent studies have shown that mucosal serotonin (5-HT) transporter (SERT) expression is decreased in animal models of colitis, as well as in the colonic mucosa of humans with ulcerative colitis and irritable bowel syndrome. Altered SERT function or expression may underlie the altered motility, secretion, and sensation seen in these inflammatory gut disorders. In an effort to elucidate possible mediators of SERT downregulation, we treated cultured colonic epithelial cells (Caco2) with conditioned medium from activated human lymphocytes. Application of the conditioned medium caused a decrease in fluoxetine-sensitive [3H]5-HT uptake. Individual proinflammatory agents were then tested for their ability to affect uptake. Cells were treated for 48 or 72 h with PGE2 (10 μM), IFN-γ (500 ng/ml), TNF-α (50 ng/ml), IL-12 (50 ng/ml), or the nitric oxide-releasing agent S-nitrosoglutathione (GSNO; 100 μM). [3H]5-HT uptake was then measured. Neither PGE nor IL-12 had any effect on [3H]5-HT uptake, and GSNO increased uptake. However, after 3-day incubation, both TNF-α and IFN-γ elicited significant decreases in SERT function. Neither TNF-α nor IFN-γ were cytotoxic when used for this period of time and at these concentrations. These two cytokines also induced decreases in SERT mRNA and protein levels. By altering SERT expression, TNF-α and IFN-γ could contribute to the altered motility and expression seen in vivo in ulcerative colitis or irritable bowel syndrome.

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