E. colipneumonia induces CD18-independent airway neutrophil migration in the absence of increased lung vascular permeability

2003 ◽  
Vol 285 (4) ◽  
pp. L879-L888 ◽  
Author(s):  
Evan S. Ong ◽  
Xiao-Pei Gao ◽  
Ning Xu ◽  
Dan Predescu ◽  
Arshad Rahman ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Vascular Injury ◽  
Lung Tissue ◽  
Neutrophil Migration ◽  
Fold Increase ◽  
Lavage Fluid ◽  
E Coli ◽  
Host Defense Response ◽  
The Relationship

We examined the relationship between neutrophil [polymorphonuclear leukocyte (PMN)] influx and lung vascular injury in response to Escherichia coli pneumonia. We assessed lung tissue PMN uptake by measuring myeloperoxidase and transvascular PMN migration by determining PMN counts in lung interstitium and bronchoalveolar lavage fluid (BALF) in mice challenged intratracheally with E. coli. Lung vascular injury was quantified by determining microvessel filtration coefficient ( Kf,c), a measure of vascular permeability. We addressed the role of CD18 integrin in the mechanism of PMN migration and lung vascular injury by inducing the expression of neutrophil inhibitory factor, a CD11/CD18 antagonist. In control animals, we observed a time-dependent sixfold increase in PMN uptake, a fivefold increase in airway PMN migration, and a 20-fold increase in interstitial PMN uptake at 6 h after challenge. Interestingly, Kf,cincreased minimally during this period of PMN extravasation. CD11/CD18 blockade reduced lung tissue PMN uptake consistent with the role of CD18 in mediating PMN adhesion to the endothelium but failed to alter PMN migration in the tissue. Moreover, CD11/CD18 blockade did not affect Kf,c. Analysis of BALF leukocytes demonstrated diminished oxidative burst compared with leukocytes from bacteremic mice, suggesting a basis for lack of vascular injury. The massive CD11/CD18-independent airway PMN influx occurring in the absence of lung vascular injury is indicative of an efficient host-defense response elicited by E. coli pneumonia.

Role of phosphatidylinositol 3-kinase-γ in mediating lung neutrophil sequestration and vascular injury induced by E. coli sepsis

2005 ◽  
Vol 289 (6) ◽  
pp. L1094-L1103 ◽  
Author(s):  
Evan Ong ◽  
Xiao-Pei Gao ◽  
Dan Predescu ◽  
Michael Broman ◽  
Asrar B. Malik
Keyword(s):  
Vascular Injury ◽  
Lung Tissue ◽  
Microvascular Permeability ◽  
Integrin Expression ◽  
Phosphatidylinositol 3 Kinase ◽  
Edema Formation ◽  
E Coli ◽  
Adhesive Proteins ◽  
Phosphatidylinositol 3

We addressed the in vivo role of phosphatidylinositol 3-kinase-γ (PI3K-γ) in signaling the sequestration of polymorphonuclear leukocytes (PMNs) in lungs and in the mechanism of inflammatory lung vascular injury. We studied mice with deletion of the p110 catalytic subunit of PI3K-γ (PI3K-γ−/− mice). We measured lung tissue PMN sequestration, microvascular permeability, and edema formation after bacteremia induced by intraperitoneal Escherichia coli challenge. PMN infiltration into the lung interstitium in PI3K-γ−/− mice as assessed morphometrically was increased 100% over that in control mice within 1 h after bacterial challenge. PI3K-γ−/− mice also developed a greater increase in lung microvascular permeability after E. coli challenge, resulting in edema formation. The augmented lung tissue PMN sequestration in PI3K-γ−/− mice was associated with increased expression of the PMN adhesive proteins CD47 and β3-integrins. We observed increased association of CD47 and β3-integrins with the extracellular matrix protein vitronectin in lungs of PI3K-γ−/− mice after E. coli challenge. PMNs from these mice also showed increased β3-integrin expression and augmented β3-integrin-dependent PMN adhesion to vitronectin. These results point to a key role of PMN PI3K-γ in negatively regulating CD47 and β3-integrin expression in gram-negative sepsis. PI3K-γ activation in PMNs induced by E. coli may modulate the extent of lung tissue PMN sequestration secondary to CD47 and β3-integrin expression. Therefore, the level of PI3K-γ activation may be an important determinant of PMN-dependent lung vascular injury.

scholarly journals The relationship between complement C3 expression and the MUC5B genotype in pulmonary fibrosis

2018 ◽  
Vol 315 (1) ◽  
pp. L1-L10 ◽  
Author(s):  
Tsukasa Okamoto ◽  
Susan K. Mathai ◽  
Corinne E. Hennessy ◽  
Laura A. Hancock ◽  
Avram D. Walts ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Lung Tissue ◽  
Complement System ◽  
Fold Increase ◽  
Complement C3 ◽  
Healthy Controls ◽  
C3 Gene ◽  
The Relationship ◽  
The Complement System

The common gain-of-function MUC5B promoter variant ( rs35705950 ) is the strongest risk factor for the development of idiopathic pulmonary fibrosis (IPF). While the role of complement in IPF is controversial, both MUC5B and the complement system play a role in lung host defense. The aim of this study was to evaluate the relationship between complement component 3 (C3) and MUC5B in patients with IPF and in bleomycin-induced lung injury in mice. To do this, we evaluated C3 gene expression in whole lung tissue from 300 subjects with IPF and 175 healthy controls. Expression of C3 was higher in IPF than healthy controls {1.40-fold increase [95% confidence interval (CI) 1.31–1.50]; P < 0.0001} and even greater among IPF subjects with the highest-risk IPF MUC5B promoter genotype [TT vs. GG = 1.59-fold (95% CI 1.15–2.20); P < 0.05; TT vs. GT = 1.66-fold (95% CI 1.20–2.30); P < 0.05]. Among subjects with IPF, C3 expression was significantly higher in the lung tissue without microscopic honeycombing than in the lung tissue with microscopic honeycombing [1.40-fold increase (95% CI 1.23– 1.59); P < 0.01]. In mice, while bleomycin exposure increased Muc5b protein expression, C3-deficient mice were protected from bleomycin-induced lung injury. In aggregate, our findings indicate that the MUC5B promoter variant is associated with higher C3 expression and suggest that the complement system may contribute to the pathogenesis of IPF.

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.

Ischemia-induced vascular changes: role of xanthine oxidase and hydroxyl radicals

1983 ◽  
Vol 245 (2) ◽  
pp. G285-G289 ◽  
Author(s):  
D. A. Parks ◽  
D. N. Granger
Keyword(s):  
Hydroxyl Radical ◽  
Dimethyl Sulfoxide ◽  
Xanthine Oxidase ◽  
Vascular Permeability ◽  
Hydroxyl Radicals ◽  
Vascular Injury ◽  
Oxygen Radicals ◽  
Intestinal Ischemia ◽  
Xanthine Oxidase Inhibitor

The results of previous studies indicate that oxygen-derived free radicals are responsible for the increased vascular permeability produced by 1 h of intestinal ischemia. The aims of this study were 1) to test the hypothesis that the enzyme xanthine oxidase is the source of oxygen radicals in the ischemic bowel and 2) to assess the role of the hydroxyl radical in the ischemia-induced vascular injury. The capillary osmotic reflection coefficient was estimated from lymphatic protein flux data in the cat ileum for the following conditions: ischemia, ischemia plus pretreatment with allopurinol (a xanthine oxidase inhibitor), and ischemia plus pretreatment with dimethyl sulfoxide (a hydroxyl radical scavenger). The increased vascular permeability produced by ischemia was largely prevented by pretreatment with either allopurinol or dimethyl sulfoxide. These findings support the hypothesis that xanthine oxidase is the source of oxygen radicals produced during ischemia. The results also indicate that hydroxyl radicals, derived from the superoxide anion, are primarily responsible for the vascular injury associated with intestinal ischemia.

Differential NF-κB activation after intratracheal endotoxin

1999 ◽  
Vol 277 (4) ◽  
pp. L823-L830 ◽  
Author(s):  
Timothy S. Blackwell ◽  
Lisa H. Lancaster ◽  
Thomas R. Blackwell ◽  
Annapurna Venkatakrishnan ◽  
John W. Christman
Keyword(s):  
Lung Tissue ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Binding Activity ◽  
Cytokine Gene Expression ◽  
Dna Binding Activity ◽  
Factor Α ◽  
The Relationship ◽  
Second Peak ◽  
Necrosis Factor

We examined the relationship between nuclear factor (NF)-κB DNA binding activity, cytokine gene expression, and neutrophilic alveolitis in rats after intratracheal (IT) instillation of endotoxin [lipopolysaccharide (LPS)]. NF-κB activation in lung tissue mirrored neutrophilic alveolitis after IT LPS instillation, with NF-κB activation and neutrophilic influx beginning 2 h after IT LPS doses of 0.01 mg/kg or greater. In lung lavage fluid cells, however, transient NF-κB activation was present in alveolar macrophages by 15 min after IT LPS instillation, followed by a second peak of NF-κB activation corresponding to the onset on neutrophilic alveolitis. For cytokines thought to be NF-κB dependent, two different patterns of mRNA expression were found. Interleukin (IL)-1α, IL-1β, and tumor necrosis factor-α showed increased mRNA by 30 min after IT LPS instillation, but IL-6- and cytokine-induced neutrophil chemoattractant mRNAs were not substantially increased until 2 h after IT LPS instillation. Therefore, IT LPS causes differential NF-κB activation in air space cells and lung tissue, which likely determines production of key cytokines and directs the evolution of neutrophilic alveolitis.

scholarly journals L-selectin deficiency decreases aortic B1a and Breg subsets and promotes atherosclerosis

2014 ◽  
Vol 112 (10) ◽  
pp. 803-811 ◽  
Author(s):  
Breanne Gjurich ◽  
Parésa Taghavie-Moghadam ◽  
Klaus Ley ◽  
Elena Galkina
Keyword(s):  
B Cells ◽  
Neutrophil Migration ◽  
Fold Increase ◽  
Interleukin 10 ◽  
Plaque Burden ◽  
Chow Diet ◽  
Blood Neutrophil ◽  
Peripheral Tissues ◽  
Cell Counts

SummaryThere is a significant recruitment of leucocytes into aortas during atherogenesis. L-selectin regulates leucocyte migration into secondary lymphoid and peripheral tissues and was proposed to play a role in leucocyte homing into aortas. Here, we determine the role of L-selectin in atherosclerosis. L-selectin-deficient Apoe -/- (Sell -/- Apoe -/-) mice had a 74% increase in plaque burden compared to Apoe -/- mice fed a chow diet for 50 weeks. Elevated atherosclerosis was accompanied by increased aortic leucocyte content, but a 50% reduction in aortic B cells despite elevated B cell counts in the blood. Follicular B cells represented 65%, whereas B1a and regulatory B cells (Breg) comprised 5% of aortic B cells. B1a and Breg cell subsets were reduced in Sell -/- Apoe -/- aortas with accompanied two-fold decrease in aortic T15 antibody and 1.2-fold decrease of interleukin-10 (IL-10) levels. L-selectin was required for B1 cell homing to the atherosclerotic aorta, as demonstrated by a 1.5-fold decrease in the migration of Sell -/- Apoe -/- vs Apoe -/- cells. Notably, we found a 1.6-fold increase in CD68hi macrophages in Sell -/- Apoe -/- compared to Apoe -/- aortas, despite comparable blood monocyte numbers and L-selectin-dependent aortic homing. L-selectin had no effect on neutrophil migration into aorta, but led to elevated blood neutrophil numbers, suggesting a potential involvement of neutrophils in atherogenesis of Sell -/- Apoe -/- mice. Thus, L-selectin deficiency increases peripheral blood neutrophil and lymphocyte numbers, decreases aortic B1a and Breg populations, T15 antibody and IL-10 levels, and increases aortic macrophage content of Sell -/- Apoe -/- mice. Altogether, these data provide evidence for an overall atheroprotective role of L-selectin.

Inactivation of CD11b in a mouse transgenic model protects against sepsis-induced lung PMN infiltration and vascular injury

2005 ◽  
Vol 21 (2) ◽  
pp. 230-242 ◽  
Author(s):  
Xiao-Pei Gao ◽  
Qinghui Liu ◽  
Michael Broman ◽  
Dan Predescu ◽  
Randall S. Frey ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Vascular Inflammation ◽  
Edema Formation ◽  
Cd11b Expression ◽  
E Coli ◽  
Transgenic Model ◽  
Microvessel Permeability ◽  
In Vivo Effects

To inactivate chronically the β2-integrin CD11b (Mac-1), we made a transgenic model in mice in which we expressed the CD11b antagonist polypeptide neutrophil inhibitory factor (NIF). Using these mice, we determined the in vivo effects of CD11b inactivation on polymorphonuclear leukocyte (PMN) function and acute lung injury (ALI) induced by Escherichia coli septicemia. In wild-type PMNs, CD11b expression was induced within 1 h after E. coli challenge, whereas this response was significantly reduced in NIF+/+ PMNs. Coimmunoprecipitation studies showed that NIF associated with CD11b in NIF+/+ PMNs. To validate the effectiveness of CD11b blockade, we compared PMN function in NIF+/+ and Mac-1-deficient (Mac-1−/−) mice. Adhesion of both Mac-1−/− and NIF+/+ PMNs to endothelial cells in response to LPS was reduced in both types of PMNs and fully blocked only by the addition of anti-CD11a monoclonal antibody. This finding is indicative of intact CD11a function in the NIF+/+ PMNs but the blockade of CD11b function. CD11b inactivation in NIF+/+ mice interfered with lung PMN infiltration induced by E. coli and prevented the increase in lung microvessel permeability and edema formation, with most of the protection seen in the 1-h period after the E. coli. Thus our results demonstrate that CD11b plays a crucial role in mediating lung PMN sequestration and vascular injury in the early phase of gram-negative septicemia. The NIF+/+ mouse model, in which CD11b is inactivated by binding to NIF, is a potentially useful model for in vivo assessment of the role of PMN CD11b in the mechanism of vascular inflammation.

scholarly journals Plasmid DNA Supercoiling and Survival in Long-Term Cultures of Escherichia coli: Role of NaCl

2003 ◽  
Vol 185 (17) ◽  
pp. 5324-5327 ◽  
Author(s):  
Annie Conter
Keyword(s):  
Escherichia Coli ◽  
Dna Supercoiling ◽  
Luria Bertani ◽  
Plasmid Pbr322 ◽  
E Coli ◽  
Topological State ◽  
Negative Supercoiling ◽  
The Relationship

ABSTRACT The relationship between the survival of Escherichia coli during long-term starvation in rich medium and the supercoiling of a reporter plasmid (pBR322) has been studied. In aerated continuously shaken cultures, E. coli lost the ability to form colonies earlier in rich NaCl-free Luria-Bertani medium than in NaCl-containing medium, and the negative supercoiling of plasmid pBR322 declined more rapidly in the absence of NaCl. Addition of NaCl at the 24th hour restored both viability and negative supercoiling in proportion to the concentration of added NaCl. Addition of ofloxacin, a quinolone inhibitor of gyrase, abolished rescue by added NaCl in proportion to the ofloxacin added. This observation raises the possibility that cells had the ability to recover plasmid supercoiling even if nutrients were not available and could survive during long-term starvation in a manner linked, at least in part, to the topological state of DNA and gyrase activity.

scholarly journals Role of the Insulin-Like Growth Factor I Decline in the Induction of Atrogin-1/MAFbx during Fasting and Diabetes

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 4806-4812 ◽  
Author(s):  
Mischael Dehoux ◽  
Ronald Van Beneden ◽  
Nevi Pasko ◽  
Pascale Lause ◽  
Josiane Verniers ◽  
...  
Keyword(s):  
Growth Factor ◽  
Effective Dose ◽  
Fold Increase ◽  
Muscle Cells ◽  
Inhibitory Effect ◽  
Physiological Concentration ◽  
Igf I ◽  
Transcriptional Effect ◽  
The Relationship

Abstract In catabolic conditions, atrogin-1/MAFbx, a muscle-specific ubiquitin-ligase required for muscle atrophy, is increased, and concentrations of IGF-I, a growth factor known to have antiproteolytic action, are reduced. To define the relationship between the decline in IGF-I and the induction of atrogin-1/MAFbx, we studied the effect of IGF-I replacement on atrogin-1/MAFbx mRNA in rats fasted for 51 h and in rats made diabetic with streptozotocin (STZ). Fasting produced a 5.8-fold increase in atrogin-1/MAFbx (P &lt; 0.001). This was attenuated to a 2.5-fold increase by injections of IGF-I (P &lt; 0.05 vs. fasting). Animals with STZ-induced diabetes experienced a 15.1-fold increase in atrogin-1/MAFbx (P &lt; 0.001). Normalization of their circulating IGF-I concentrations by IGF-I infusion blunted the induction of atrogin-1/MAFbx to 6.3-fold (P &lt; 0.05 vs. STZ diabetes without IGF-I). To further delineate the regulation of atrogin-1/MAFbx by IGF-I, we studied a model of cultured muscle cells. We observed that IGF-I produced a time- and dose-dependent reduction of atrogin-1/MAFbx mRNA, with a 50% effective dose of 5 nm IGF-I, a physiological concentration. The degradation rate of atrogin-1/MAFbx mRNA was not affected by IGF-I, suggesting that the reduction of atrogin-1/MAFbx mRNA by IGF-I is a transcriptional effect. Exposure of muscle cells in culture to dexamethasone increased atrogin-1/MAFbx mRNA with a 50% effective dose of 10 nm, a pharmacological concentration. In the presence of dexamethasone, IGF-I at physiological concentrations retained its full inhibitory effect on atrogin-1/MAFbx mRNA. We conclude that IGF-I inhibits atrogin-1/MAFbx expression and speculate that this effect might contribute to the antiproteolytic action of IGF-I in muscle.

scholarly journals Inhibition of Prostaglandin F2α Receptors Exaggerates HCl-Induced Lung Inflammation in Mice

2021 ◽  
Vol 22 (23) ◽  
pp. 12843
Author(s):  
Toko Maehara ◽  
Ko Fujimori
Keyword(s):  
Umbilical Vein ◽  
Lung Surfactant ◽  
Neutrophil Migration ◽  
Prostaglandin F2α ◽  
Lavage Fluid ◽  
Clinical Feature ◽  
Lung Edema ◽  
Induced Expression ◽  
Respiratory Dysfunction

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory disorders that are caused by aspiration, sepsis, trauma, and pneumonia. A clinical feature of ALI/ARDS is the acute onset of severe hypoxemia, and the mortality rate, which is estimated at 38–50%, remains high. Although prostaglandins (PGs) are detected in the bronchoalveolar lavage fluid of patients with ALI/ARDS, the role of PGF2α in ALI remains unclear. We aimed to clarify the role of PGF2α/PGF2α receptor (FP) signaling in acid-induced ALI using an FP receptor antagonist, AL8810. Intratracheal injection of hydrochloric acid (HCl) increased neutrophil migration into the lungs, leading to respiratory dysfunction. Pre-administration of AL8810 further increased these features. Moreover, pre-treatment with AL8810 enhanced the HCl-induced expression of pro-inflammatory cytokines and neutrophil migratory factors in the lungs. Administration of HCl decreased the gene expression of lung surfactant proteins, which was further reduced by co-administration of AL8810. Administration of AL8810 also increased lung edema and reduced mRNA expression of epithelial sodium channel in the lungs, indicating that AL8810 reduced fluid clearance. Furthermore, AL8810 also increased lipopolysaccharide-induced expression of adhesion molecules such as intracellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells. These results indicate that inhibition of FP receptors by AL8810 exacerbated HCl-induced ALI.

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