Pneumocystis carinii infection sensitizes lung to radiation-induced injury after syngeneic marrow transplantation: role of CD4+ T cells

2006 ◽  
Vol 290 (6) ◽  
pp. L1087-L1096 ◽  
Author(s):  
Lauren Bruckner ◽  
Francis Gigliotti ◽  
Terry Wright ◽  
Allen Harmsen ◽  
Robert H. Notter ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Injury ◽  
Pneumocystis Carinii ◽  
Lavage Fluid ◽  
Marrow Transplant ◽  
Lung Compliance ◽  
Pulmonary Dysfunction ◽  
Tnf Α ◽  
Total Body

A murine model of bone marrow transplant (BMT)-related lung injury was developed to study how infection sensitizes lung to the damaging effects of total body irradiation (TBI) at infectious and TBI doses that individually do not cause injury. Mice infected with Pneumocystis carinii exhibited an asymptomatic, rapid, and transient influx of eosinophils and T cells in bronchoalveolar lavage fluid (BALF). In contrast, mice infected with P. carinii 7 days before receiving TBI and syngeneic BMT ( P. carinii/TBI mice) exhibited severe pulmonary dysfunction, surfactant aggregate depletion, and surfactant activity reductions at 17 days post-BMT. BALF from P. carinii/TBI mice contained a disproportionate initial influx of CD4+ T cells (CD4+:CD8+ ratio of 2.7) that correlated with progressive lung injury (from 8 to 17 days post-BMT). Levels of TNF-α in BALF were significantly increased in P. carinii/TBI mice compared with mice given either insult alone, with peak values found at 11 days post-BMT. In vivo depletion of CD4+ T cells in P. carinii/TBI mice abrogated pulmonary dysfunction and reduced TNF-α levels in BALF, whereas depletion of CD8+ T cells did not affect lung compliance or TNF-α. Lung injury was not attributable to direct P. carinii damage, since CD4-depleted P. carinii/TBI mice that exhibited no injury had higher average lung P. carinii burdens than either mice given P. carinii alone or undepleted P. carinii/TBI mice. Together, these results indicate that P. carinii infection can sensitize the lung to subsequent TBI-mediated lung injury via a process dependent on non-alloreactive CD4+ T cells.

In vivo anti-inflammatory action of eugenol on lipopolysaccharide-induced lung injury

2010 ◽  
Vol 108 (4) ◽  
pp. 845-851 ◽  
Author(s):  
Clarissa B. Magalhães ◽  
Douglas R. Riva ◽  
Leonardo J. DePaula ◽  
Aline Brando-Lima ◽  
Vera Lúcia G. Koatz ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lavage Fluid ◽  
Nuclear Factor Κb ◽  
Tissue Expression ◽  
The Other ◽  
Alveolar Collapse ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Inflammatory Action

Eugenol, a methoxyphenol component of clove oil, suppresses cyclooxygenase-2 expression, while eugenol dimers prevent nuclear factor-κB (NF-κB) activation and inflammatory cytokine expression in lipopolysaccharide-stimulated macrophages. Our aim was to examine the in vivo anti-inflammatory effects of eugenol. BALB/c mice were divided into four groups. Mice received saline [0.05 ml intratracheally (it), control (Ctrl) and eugenol (Eug) groups] or Escherichia coli LPS (10 μg it, LPS and LPSEug groups). After 6 h, mice received saline (0.2 ml ip, Ctrl and LPS groups) or eugenol (160 mg/kg ip, Eug and LPSEug groups). Twenty-four hours after LPS injection, pulmonary resistive (ΔP1) and viscoelastic (ΔP2) pressures, static elastance (Est), and viscoelastic component of elastance (ΔE) were measured. Lungs were prepared for histology. In parallel mice, bronchoalveolar lavage fluid was collected 24 h after LPS injection. TNF-α was determined by ELISA. Lung tissue expression of NF-κB was determined by EMSA. ΔP1, ΔP2, Est, and ΔE were significantly higher in the LPS group than in the other groups. LPS mice also showed significantly more alveolar collapse, collagen fibers, and neutrophil influx and higher TNF-α levels and NF-κB expression than the other groups. Eugenol treatment reduced LPS-induced lung inflammation, improving lung function. Our results suggest that eugenol exhibits in vivo anti-inflammatory action in LPS-induced lung injury.

scholarly journals Sensitized CD8+ T Cells Fail To Control Organism Burden but Accelerate the Onset of Lung Injury during Pneumocystis carinii Pneumonia

2006 ◽  
Vol 74 (11) ◽  
pp. 6310-6316 ◽  
Author(s):  
Francis Gigliotti ◽  
Elliott L. Crow ◽  
Samir P. Bhagwat ◽  
Terry W. Wright
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Injury ◽  
Mouse Model ◽  
Cd8 T Cells ◽  
Scid Mouse ◽  
Pneumocystis Carinii ◽  
Rapid Onset ◽  
Scid Mouse Model

ABSTRACT While CD8+ cells have been shown to contribute to lung injury during Pneumocystis carinii pneumonia (PCP), there are conflicting reports concerning the ability of CD8+ cells to kill P. carinii. To address these two issues, we studied the effect of the presence of CD8+ cells in two mouse models of PCP. In the reconstituted SCID mouse model, depletion of CD8+ cells in addition to CD4+ cells after reconstitution did not result in increased numbers of P. carinii cysts compared to the numbers of cysts in mice with only CD4+ cells depleted. This result was observed regardless of whether the mice were reconstituted with naïve or P. carinii-sensitized lymphocytes. In contrast, reconstitution with sensitized lymphocytes resulted in more rapid onset of lung injury that was dependent on the presence of CD8+ cells. The course of organism replication over a 6-week period was also examined in the CD4+-T-cell-depleted and CD4+- and CD8+-T-cell-depleted mouse model of PCP. Again, the organism burdens were identical at all times regardless of whether CD8+ cells were present. Thus, in the absence of CD4+ T cells, CD8+ T cells are a key contributor to the inflammatory lung injury associated with PCP. However, we were unable to demonstrate an in vivo effect of these cells on the course of P. carinii infection.

scholarly journals High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury

2003 ◽  
Vol 95 (4) ◽  
pp. 1385-1393 ◽  
Author(s):  
Michael R. Wilson ◽  
Sharmila Choudhury ◽  
Michael E. Goddard ◽  
Kieran P. O'Dea ◽  
Andrew G. Nicholson ◽  
...  
Keyword(s):  
Lung Injury ◽  
Mouse Model ◽  
Tidal Volume ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
High Tidal Volume ◽  
Lung Pathology ◽  
Ventilator Induced Lung Injury ◽  
Tnf Α

Mechanical ventilation has been demonstrated to exacerbate lung injury, and a sufficiently high tidal volume can induce injury in otherwise healthy lungs. However, it remains controversial whether injurious ventilation per se, without preceding lung injury, can initiate cytokine-mediated pulmonary inflammation. To address this, we developed an in vivo mouse model of acute lung injury produced by high tidal volume (Vt) ventilation. Anesthetized C57BL6 mice were ventilated at high Vt (34.5 ± 2.9 ml/kg, mean ± SD) for a duration of 156 ± 17 min until mean blood pressure fell below 45 mmHg ( series 1); high Vt for 120 min ( series 2); or low Vt (8.8 ± 0.5 ml/kg) for 120 or 180 min ( series 3). High Vt produced progressive lung injury with a decrease in respiratory system compliance, increase in protein concentration in lung lavage fluid, and lung pathology showing hyaline membrane formation. High-Vt ventilation was associated with increased TNF-α in lung lavage fluid at the early stage of injury ( series 2) but not the later stage ( series 1). In contrast, lavage fluid macrophage inflammatory protein-2 (MIP-2) was increased in all high-Vt animals. Lavage fluid from high-Vt animals contained bioactive TNF-α by WEHI bioassay. Low-Vt ventilation induced minimal changes in physiology and pathology with negligible TNF-α and MIP-2 proteins and TNF-α bioactivity. These results demonstrate that high-Vt ventilation in the absence of underlying injury induces intrapulmonary TNF-α and MIP-2 expression in mice. The apparently transient nature of TNF-α upregulation may help explain previous controversy regarding the involvement of cytokines in ventilator-induced lung injury.

scholarly journals Celastrol alleviates LPS-induced inflammation in BMDMs and acute lung injury in mice via inhibition of p-38 MAPK/MK2 signaling

2021 ◽  
Vol 19 ◽  
pp. 205873922110205
Author(s):  
Zhengxu Chen ◽  
Xinyi Yang ◽  
Lu Zhang ◽  
Man Li ◽  
Lei Sun ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
P38 Mapk ◽  
Lavage Fluid ◽  
Lung Edema ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Objective: Celastrol is a compound extracted from a medicinal plant Tripterygium wilfordii which has a broad-spectrum anti-inflammatory effect in traditional medicine. However, the effect of celastrol on acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is still unknown. Methods: We reported that celastrol alleviated LPS-induced acute lung injury by H&E staining, MPO activity and the expression of cytokines in broncho-alveolar lavage fluid. The effect of celastrol on bone marrow-derived macrophages (BMDMs) after LPS treatment was measured by ELISA and Western blotting. Results: In vivo, celastrol reduced the LPS-induced lung edema and MPO activity of lung tissue. Furthermore, the production of inflammatory cytokines IL-6, TNF-α, and KC in bronchoalveolar lavage was reduced. In vitro, upon treatment of LPS, celastrol dose-dependently inhibited the expression of iNOS in BMDMs. Meanwhile, the expression of IL-6, TNF-α, and KC in BMDMs were also inhibited by celastrol treatment. Furthermore, we found that celastrol attenuated the phosphorylation of p38 MAPK and MK2, and inhibited the interaction between p38 MAPK and MK2. Conclusion: Our data indicate that celastrol has an anti-inflammatory effect on LPS-induced inflammatory response in vivo and in vitro, suggesting celastrol is a promising compound for the treatment of ALI and ARDS.

Morin Promotes the Production of Th2 Cytokine by Modulating Bone Marrow-Derived Dendritic Cells

2006 ◽  
Vol 34 (04) ◽  
pp. 667-684 ◽  
Author(s):  
Chia-Yang Li ◽  
Jau-Ling Suen ◽  
Bor-Luen Chiang ◽  
Pei-Dawn Lee Chao ◽  
Shih-Hua Fang
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Interleukin 12 ◽  
Th2 Response ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Th Differentiation ◽  
Th1 And Th2 Responses

Our previous studies had reported that morin decreased the interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-α) production in lipopolysaccharide (LPS)-activated macrophages, suggesting that morin may promote helper T type 2 (Th2) response in vivo. Dendritic cells (DCs) are the most potent antigen presenting cells and known to play a major role in the differentiation of helper T type 1 (Th1) and Th2 responses. This study aimed to reveal whether morin is able to control the Th differentiation through modulating the maturation and functions of DCs. Bone marrow-derived dendritic cells (BM-DCs) were incubated with various concentrations of morin and their characteristics were studied. The results indicated that morin significantly affects the phenotype and cytokine expression of BM-DCs. Morin reduced the production of IL-12 and TNF-α in BM-DCs, in response to LPS stimulation. In addition, the proliferative response of stimulated alloreactive T cells was significantly decreased by morin in BM-DCs. Furthermore, allogeneic T cells secreted higher IL-4 and lower IFN-γ in response to morin in BM-DCs. In conclusion, these results suggested that morin favors Th2 cell differentiation through modulating the maturation and function of BM-DCs.

scholarly journals Endothelial Rap1B mediates T-cell exclusion to promote tumor growth -a novel mechanism underlying vascular immunosuppression

2021 ◽  
Author(s):  
Guru Prasad Sharma ◽  
Ramoji Kosuru ◽  
Sribalaji Lakshmikanthan ◽  
Shikan Zheng ◽  
Yao Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Small Gtpase ◽  
Vascular Endothelial ◽  
Promote Tumor Growth ◽  
Tnf Α ◽  
Inflammatory Stimuli ◽  
Endothelial Growth Factor

Overcoming vascular immunosuppression: lack of endothelial cell (EC) responsiveness to inflammatory stimuli in the proangiogenic environment of tumors, is essential for successful cancer immunotherapy. The mechanisms through which Vascular Endothelial Growth Factor (VEGF) modulates tumor EC response to exclude T cells are not well understood. The goal was to determine the role of EC Rap1B, a small GTPase that positively regulates VEGFangiogenesis during development, in tumor growth in vivo. Using mouse models of Rap1B deficiency, Rap1B+/- and EC-specific Rap1B KO (Rap1BiΔEC) we demonstrate that EC Rap1B restricts tumor growth and angiogenesis. More importantly, EC-specific Rap1B deletion leads to an altered tumor microenvironment with increased recruitment of leukocytes and increased activity of tumor CD8+ T cells. We find that tumor growth, albeit not angiogenesis, is restored in Rap1BiΔEC mice by depleting CD8+ T cells. Mechanistically, global transcriptome analysis indicated upregulation of the tumor cytokine, TNF-α, -induced signaling and NFκB transcriptional activity in Rap1B-deficient ECs. Functionally, EC Rap1B deletion led to upregulation of NFκB activity and enhanced Cell Adhesion Molecules (CAMs) expression in TNF-α stimulated ECs. Importantly, CAM expression was upregulated also in tumor ECs from Rap1BiΔEC mice, vs. controls. Significantly, deletion of Rap1B abrogated VEGF immunosuppressive downregulation of CAM expression, demonstrating that Rap1B is essential for VEGF-suppressive signaling. Thus, our studies identify a novel endothelial-endogenous mechanism underlying VEGF-dependent desensitization of EC to pro-inflammatory stimuli. Significantly, they identify EC Rap1 as a potential novel vascular target in cancer immunotherapy.

scholarly journals Repetitive Injections of Dendritic Cells Matured with Tumor Necrosis Factor α Induce Antigen-specific Protection of Mice from Autoimmunity

2001 ◽  
Vol 195 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Mauritius Menges ◽  
Susanne Rößner ◽  
Constanze Voigtländer ◽  
Heike Schindler ◽  
Nicole A. Kukutsch ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cell Immunity ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Mature dendritic cells (DCs) are believed to induce T cell immunity, whereas immature DCs induce T cell tolerance. Here we describe that injections of DCs matured with tumor necrosis factor (TNF)-α (TNF/DCs) induce antigen-specific protection from experimental autoimmune encephalomyelitis (EAE) in mice. Maturation by TNF-α induced high levels of major histocompatibility complex class II and costimulatory molecules on DCs, but they remained weak producers of proinflammatory cytokines. One injection of such TNF/DCs pulsed with auto-antigenic peptide ameliorated the disease score of EAE. This could not be observed with immature DCs or DCs matured with lipopolysaccharide (LPS) plus anti-CD40. Three consecutive injections of peptide-pulsed TNF/DCs derived from wild-type led to the induction of peptide-specific predominantly interleukin (IL)-10–producing CD4+ T cells and complete protection from EAE. Blocking of IL-10 in vivo could only partially restore the susceptibility to EAE, suggesting an important but not exclusive role of IL-10 for EAE prevention. Notably, the protection was peptide specific, as TNF/DCs pulsed with unrelated peptide could not prevent EAE. In conclusion, this study describes that stimulation by TNF-α results in incompletely matured DCs (semi-mature DCs) which induce peptide-specific IL-10–producing T cells in vivo and prevent EAE.

scholarly journals ADAM17-Mediated Processing of TNF-α Expressed by Antiviral Effector CD8+ T Cells Is Required for Severe T-Cell-Mediated Lung Injury

PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e79340 ◽  
Author(s):  
Matthew P. DeBerge ◽  
Kenneth H. Ely ◽  
Guang-Shing Cheng ◽  
Richard I. Enelow
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Injury ◽  
Cd8 T Cells ◽  
Tnf Α

scholarly journals Premobilization of CD133+ progenitors is associated with attenuated inflammation-induced pulmonary dysfunction following extracorporeal circulation in mice

2020 ◽  
Vol 31 (2) ◽  
pp. 210-220
Author(s):  
Dan Luo ◽  
Xinhao Liu ◽  
Jie Zhang ◽  
Lei Du ◽  
Lin Bai ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Lung Tissue ◽  
Extracorporeal Circulation ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Pulmonary Dysfunction

Abstract OBJECTIVES Progenitor cells mobilized by granulocyte colony-stimulating factor (G-CSF) have been shown to lessen acute kidney injury induced by extracorporeal circulation (ECC). Both acute kidney injury and lung injury are characterized by endothelial dysfunction. Our goal was to examine whether and how G-CSF-mobilized progenitors with endothelial capacity may help mitigate ECC-induced pulmonary dysfunction. METHODS G-CSF (10 μg/kg/day) was administered subcutaneously to C57BL/6 mice before or at the initiation of the ECC process, after which lung injury was assessed by measuring neutrophils in the fluid from bronchoalveolar lavage and determining the pathological score in lung tissue. CD133+ progenitors were isolated and injected into C57BL/6 mice before ECC in vivo. We incubated the CD133+ cells with pulmonary monocytes or neutrophils isolated from naïve mice in vitro. RESULTS Pretreatment with G-CSF for 2 days significantly decreased the number of neutrophils in the bronchoalveolar lavage fluid, and the pathological score (P < 0.01; n = 5) improved the PaO2/FiO2 ratio [193.4 ± 12.7 (ECC without G-CSF) vs 305.6 ± 22.6 mmHg (ECC with G-CSF); P = 0.03, n = 5] and suppressed neutrophil elastase and tumour necrosis factor-α levels in the circulation; we also observed increases in both circulating and pulmonary populations of CD133+ progenitors. Similar effects were observed in animals pretreated with CD133+ progenitors instead of G-CSF before ECC. The majority of CD133+/CD45− and CD133+/CD45+ progenitors were mobilized in the lung and in the circulation, respectively. Incubating CD133+ progenitors with neutrophils or pulmonary monocytes blocked lipopolysaccharide-induced release of inflammatory factors. CONCLUSIONS Our results suggest that pretreatment of G-CSF attenuates ECC-induced pulmonary dysfunction through inhibiting the inflammatory response in lung tissue and in the circulation with associated premobilization of CD133+ progenitors.

scholarly journals The Role of Interleukin-10 (IL-10) in IL-15–Mediated T-Cell Responses

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4513-4521 ◽  
Author(s):  
Dieter Körholz ◽  
Ursula Banning ◽  
Halvard Bönig ◽  
Markus Grewe ◽  
Marion Schneider ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Interleukin 10 ◽  
T Cell Proliferation ◽  
Cell Production ◽  
Cd25 Expression ◽  
Tnf Α ◽  
Ifn Γ

Abstract Interleukin-15 (IL-15) is a potent T-cell stimulating factor, which has recently been used for pre-clinical in vivo immunotherapy. Here, the IL-15 effect on CD3-stimulated peripheral human T cells was investigated. IL-15 induced a significant T-cell proliferation and upregulated CD25 expression. IL-15 significantly enhanced T-cell production of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-10. Between 10- and 100-fold greater concentrations of IL-15 were necessary to reach a biological effect equivalent to that of IL-2. Blockade of IL-2 binding to the high-affinity IL-2 receptor did not affect the IL-15 effects, suggesting that IL-15 did not act by inducing endogenous IL-2. Exogenously administered IL-10 significantly reduced the IL-15 and IL-2–mediated IFN-γ and TNF-α production, whereas T-cell proliferation and CD25 expression were not affected. The inhibitory effects of exogenously administered IL-10 on T-cell cytokine production appeared indirect, and are likely secondary to decreased IL-12 production by accessory cells. Inhibition of endogenous IL-10 binding to the IL-10 receptor significantly increased IFN-γ and TNF-α release from T cells. These data suggest that endogenous IL-10 can regulate activated T-cell production of IFN-γ and TNF-α via a paracrine negative feedback loop. The observations of this study could be of relevance for the therapeutic use of IL-15 in vivo.

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