TLR4 regulates Kupffer cell chemokine production, systemic inflammation and lung neutrophil infiltration following trauma-hemorrhage

2007 ◽  
Vol 44 (10) ◽  
pp. 2625-2630 ◽  
Author(s):  
Michael Frink ◽  
Ya-Ching Hsieh ◽  
Bjoern M. Thobe ◽  
Mashkoor A. Choudhry ◽  
Martin G. Schwacha ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Kupffer Cell ◽  
Neutrophil Infiltration ◽  
Chemokine Production

17β-Estradiol inhibits keratinocyte-derived chemokine production following trauma-hemorrhage

2007 ◽  
Vol 292 (2) ◽  
pp. L585-L591 ◽  
Author(s):  
Michael Frink ◽  
Bjoern M. Thobe ◽  
Ya-Ching Hsieh ◽  
Mashkoor A. Choudhry ◽  
Martin G. Schwacha ◽  
...  
Keyword(s):  
Kupffer Cell ◽  
Neutrophil Infiltration ◽  
Organ Damage ◽  
Sham Operation ◽  
Myeloperoxidase Activity ◽  
Edema Formation ◽  
Chemokine Production ◽  
Cell Production ◽  
Tnf Α ◽  
17Β Estradiol

Neutrophil infiltration is a key step in the development of organ dysfunction following trauma-hemorrhage (T-H). Although we have previously shown that 17β-estradiol (E2) prevents neutrophil infiltration and organ damage following T-H, the mechanism by which E2 inhibits neutrophil transmigration remains unknown. We hypothesized that E2 prevents neutrophil infiltration via modulation of keratinocyte-derived chemokine (KC), a major attractant for neutrophils. To examine this, male C3H/HeN mice were subjected to T-H or sham operation and thereafter resuscitated with Ringer lactate and E2 (1 mg/kg body wt) or vehicle. Animals were killed 2 h after resuscitation, and Kupffer cells were isolated. Plasma levels and Kupffer cell production capacities of KC, TNF-α, and IL-6 were determined by BD Cytometric Bead Arrays; lung mRNA expression of KC was measured with real-time PCR; myeloperoxidase activity assays were performed to determine neutrophil infiltration, and organ damage was assessed by edema formation. Treatment with E2 decreased systemic levels and restored Kupffer cell production of KC, TNF-α, and IL-6, as well as KC gene expression and protein in the lung. This was accompanied with a decrease in neutrophil infiltration and edema formation in the lung. These results suggest that E2 prevents lung neutrophil infiltration and organ damage in part by decreasing KC during posttraumatic immune response.

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.

scholarly journals Increased Survival and Reduced Neutrophil Infiltration of the Liver in Rab27a- but Not Munc13-4-Deficient Mice in Lipopolysaccharide-Induced Systemic Inflammation

2011 ◽  
Vol 79 (9) ◽  
pp. 3607-3618 ◽  
Author(s):  
Jennifer L. Johnson ◽  
Hong Hong ◽  
Jlenia Monfregola ◽  
Sergio D. Catz
Keyword(s):  
Systemic Inflammation ◽  
Bacterial Infections ◽  
Neutrophil Infiltration ◽  
Cd11b Expression ◽  
Necrosis Factor Alpha ◽  
Neutrophil Sequestration ◽  
Impaired Liver ◽  
Granule Secretion ◽  
Deficient Mice

ABSTRACTGenetic defects in theRab27aorMunc13-4gene lead to immunodeficiencies in humans, characterized by frequent viral and bacterial infections. However, the role of Rab27a and Munc13-4 in the regulation of systemic inflammation initiated by Gram-negative bacterium-derived pathogenic molecules is currently unknown. Using a model of lipopolysaccharide-induced systemic inflammation, we show that Rab27a-deficient (Rab27aash/ash) mice are resistant to lipopolysaccharide (LPS)-induced death, while Munc13-4-deficient (Munc13-4jinx/jinx) mice show only moderate protection. Rab27aash/ashbut not Munc13-4jinx/jinxmice showed significantly decreased tumor necrosis factor alpha (TNF-α) plasma levels after LPS administration. Neutrophil sequestration in lungs from Rab27aash/ashand Munc13-4jinx/jinxLPS-treated mice was similar to that observed for wild-type mice. In contrast, Rab27a- but not Munc13-4-deficient mice showed decreased neutrophil infiltration in liver and failed to undergo LPS-induced neutropenia. Decreased liver infiltration in Rab27aash/ashmice was accompanied by lower CD44 but normal CD11a and CD11b expression in neutrophils. Both Rab27a- and Munc13-4-deficient mice showed decreased azurophilic granule secretionin vivo, suggesting that impaired liver infiltration and improved survival in Rab27aash/ashmice is not fully explained by deficient exocytosis of this granule subset. Altogether, our data indicate that Rab27a but not Munc13-4 plays an important role in neutrophil recruitment to liver and LPS-induced death during endotoxemia, thus highlighting a previously unrecognized role for Rab27a in LPS-mediated systemic inflammation.

scholarly journals TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration

2008 ◽  
Vol 14 (7) ◽  
pp. 738-747 ◽  
Author(s):  
Shinichiro Yamamoto ◽  
Shunichi Shimizu ◽  
Shigeki Kiyonaka ◽  
Nobuaki Takahashi ◽  
Teruaki Wajima ◽  
...  
Keyword(s):  
Neutrophil Infiltration ◽  
Chemokine Production

Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage

2007 ◽  
Vol 292 (5) ◽  
pp. L1227-L1232 ◽  
Author(s):  
Ya-Ching Hsieh ◽  
Michael Frink ◽  
Chi-Hsun Hsieh ◽  
Mashkoor A. Choudhry ◽  
Martin G. Schwacha ◽  
...  
Keyword(s):  
Lung Injury ◽  
Migration Inhibitory Factor ◽  
Tissue Damage ◽  
Neutrophil Infiltration ◽  
Organ Damage ◽  
Inhibitory Factor ◽  
Sham Operation ◽  
Protective Effects ◽  
Chemokine Production ◽  
Monocyte Chemoattractant Protein 1

Although studies have shown that 17β-estradiol (E2) prevents neutrophil infiltration and organ damage following trauma-hemorrhage, the mechanism by which E2inhibits neutrophil transmigration remains unknown. Macrophage migration inhibitory factor (MIF) is thought to play a central role in exacerbation of inflammation and is associated with lung injury. MIF regulates the inflammatory response through modulation of Toll-like receptor 4 (TLR4). Activation of TLR4 results in the release of proinflammatory cytokines and chemokines, which induce neutrophil infiltration and subsequent tissue damage. We hypothesized that E2mediates its salutary effects in the lung following trauma-hemorrhage via negative regulation of MIF and modulation of TLR4 and cytokine-induced chemotaxis. C3H/HeOuJ mice were subjected to trauma-hemorrhage (mean blood pressure 35 ± 5 mmHg for ∼90 min, then resuscitation) or sham operation. Mice received vehicle, E2, or E2in combination with recombinant mouse MIF protein (rMIF). Trauma-hemorrhage increased lung MIF and TLR4 protein levels as well as lung and systemic levels of cytokines/chemokines. Treatment of animals with E2following trauma-hemorrhage prevented these changes. However, administration of rMIF protein with E2abolished the E2-mediated decrease in lung TLR4 levels, lung and plasma levels of IL-6, TNF-α, monocyte chemoattractant protein-1, and keratinocyte-derived chemokine (KC). Administration of rMIF protein also prevented E2-mediated reduction in neutrophil influx and tissue damage in the lungs following trauma-hemorrhage. These results suggest that the protective effects of E2on lung injury following trauma-hemorrhage are mediated via downregulation of lung MIF and TLR4-induced cytokine/chemokine production.

scholarly journals Kupffer cell depletion partially prevents hepatic heme oxygenase 1 messenger RNA accumulation in systemic inflammation in mice: Role of interleukin 1?

Hepatology ◽  
1998 ◽  
Vol 27 (3) ◽  
pp. 703-710 ◽  
Author(s):  
Milena Rizzardini ◽  
Massimo Zappone ◽  
Pia Villa ◽  
Paola Gnocchi ◽  
Marina Sironi ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Systemic Inflammation ◽  
Kupffer Cell ◽  
Messenger Rna ◽  
Interleukin 1 ◽  
Cell Depletion ◽  
Heme Oxygenase 1 ◽  
Rna Accumulation

scholarly journals Acetylated Diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol in Autoimmune Arthritis and Interstitial Lung Disease in SKG Mice

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1095
Author(s):  
Doo-Ho Lim ◽  
Eun-Ju Lee ◽  
Hee-Seop Lee ◽  
Do Hoon Kim ◽  
Jae-Hyun Lee ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Endothelial Permeability ◽  
Neutrophil Infiltration ◽  
Immunofluorescent Staining ◽  
Autoimmune Arthritis ◽  
Arthritis Score ◽  
Neutrophil Accumulation ◽  
Chemokine Production ◽  
Lipid Molecule

Acetylated diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) is a lipid molecule from the antlers of sika deer that might reduce inflammation by effectively controlling neutrophil infiltration, endothelial permeability and inflammatory chemokine production. Therefore, we evaluated the modulatory effect of PLAG on arthritis and interstitial lung disease (ILD) in an autoimmune arthritis model. We injected curdlan into SKG mice and PLAG was orally administered every day from 3 weeks to 20 weeks after the curdlan injection. The arthritis score was measured every week after the curdlan injection. At 20 weeks post-injection, the lung specimens were evaluated with H&E, Masson’s trichrome and multiplexed immunofluorescent staining. Serum cytokines were also analyzed using a Luminex multiple cytokine assay. PLAG administration decreased the arthritis score until 8 weeks after the curdlan injection. However, the effect was not sustained thereafter. A lung histology revealed severe inflammation and fibrosis in the curdlan-induced SKG mice, which was attenuated in the PLAG-treated mice. Furthermore, immunofluorescent staining of the lung tissue showed a GM-CSF+ neutrophil accumulation and a decreased citrullinated histone 3 expression after PLAG treatment. PLAG also downregulated the levels of IL-6 and TNF-α and upregulated the level of sIL-7Rα, an anti-fibrotic molecule. Our results indicate that PLAG might have a preventative effect on ILD development through the resolution of NETosis in the lung.

scholarly journals Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis

2021 ◽  
Vol 22 (23) ◽  
pp. 12923
Author(s):  
Zhiyi Ding ◽  
Feifei Du ◽  
Richard Garland Averitt V ◽  
Gabriel Jakobsson ◽  
Carl-Fredrik Rönnow ◽  
...  
Keyword(s):  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Abdominal Sepsis ◽  
Neutrophil Activation ◽  
Neutrophil Recruitment ◽  
Lung Damage ◽  
Edema Formation ◽  
Chemokine Production ◽  
Activated Complex

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.

17,18-Epoxyeicosatetraenoic Acid Inhibits TNF-α-Induced Inflammation in Cultured Human Airway Epithelium and LPS-Induced Murine Airway Inflammation

2021 ◽  
pp. 194589242110276
Author(s):  
Shiori Hara ◽  
Ichiro Tojima ◽  
Shino Shimizu ◽  
Hideaki Kouzaki ◽  
Takeshi Shimizu
Keyword(s):  
Epithelial Cells ◽  
Airway Inflammation ◽  
Neutrophil Infiltration ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Mucus Production ◽  
Chemokine Production ◽  
In Vivo Effects

Background 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE), an eicosapentaenoic acid metabolite, is generated from dietary oil in the gut, and antiinflammatory activity of 17,18-EpETE was recently reported. Objective To evaluate the inhibitory effects of 17,18-EpETE in airway inflammation, we examined in vitro and in vivo effects on mucus production, neutrophil infiltration, and cytokine/chemokine production in airway epithelium. Methods Nasal tissue localization of G protein-coupled receptor 40 (GPR40), a receptor of 17,18-EpETE, was determined by immunohistochemical staining. Expression of GPR40 mRNA in nasal mucosa of chronic rhinosinusitis (CRS) patients and control subjects was determined by reverse transcription-polymerase chain reaction (RT-PCR). The in vitro effects on airway epithelial cells were examined using normal human bronchial epithelial cells and NCI-H292 cells. To examine the in vivo effects of 17,18-EpETE on airway inflammation, we induced goblet cell metaplasia, mucus production, and neutrophil infiltration in mouse nasal epithelium by intranasal lipopolysaccharide (LPS) instillation. Results GPR40 is mainly expressed in human nasal epithelial cells and submucosal gland cells. RT-PCR analysis revealed that the expression of GPR40 mRNA was increased in nasal tissues from CRS patients compared with those from control subjects. 17,18-EpETE significantly inhibited tumor necrosis factor (TNF)-α-induced production of interleukin (IL)-6 , IL-8, and mucin from cultured human airway epithelial cells dose dependently, and these antiinflammatory effects on cytokine production were abolished by GW1100, a selective GPR40 antagonist. Intraperitoneal injection or intranasal instillation of 17,18-EpETE significantly attenuated LPS-induced mucus production and neutrophil infiltration in mouse nasal epithelium. Inflammatory cytokine/chemokine production in lung tissues and bronchoalveolar lavage fluids was also inhibited. Conclusion These results indicate that 17,18-EpETE plays a regulatory role in mucus hypersecretion and neutrophil infiltration in nasal inflammation. Local or systemic administration may provide a new therapeutic approach for the treatment of intractable airway disease such as CRS.

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