Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice

Patients with acute kidney injury (AKI) have increased serum proinflammatory cytokines and an increased occurrence of respiratory complications. The aim of the present study was to examine the effect of renal and extrarenal cytokine production on AKI-mediated lung injury in mice. C57Bl/6 mice underwent sham surgery, splenectomy, ischemic AKI, or ischemic AKI with splenectomy and kidney, spleen, and liver cytokine mRNA, serum cytokines, and lung injury were examined. The proinflammatory cytokines IL-6, CXCL1, IL-1β, and TNF-α were increased in the kidney, spleen, and liver within 6 h of ischemic AKI. Since splenic proinflammatory cytokines were increased, we hypothesized that splenectomy would protect against AKI-mediated lung injury. On the contrary, splenectomy with AKI resulted in increased serum IL-6 and worse lung injury as judged by increased lung capillary leak, higher lung myeloperoxidase activity, and higher lung CXCL1 vs. AKI alone. Splenectomy itself was not associated with increased serum IL-6 or lung injury vs. sham. To investigate the mechanism of the increased proinflammatory response, splenic production of the anti-inflammatory cytokine IL-10 was determined and was markedly upregulated. To confirm that splenic IL-10 downregulates the proinflammatory response of AKI, IL-10 was administered to splenectomized mice with AKI, which reduced serum IL-6 and improved lung injury. Our data demonstrate that AKI in the absence of a counter anti-inflammatory response by splenic IL-10 production results in an exuberant proinflammatory response and lung injury.

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Vanillin protects lipopolysaccharide-induced acute lung injury by inhibiting ERK1/2, p38 and NF-κB pathway

Future Medicinal Chemistry ◽

10.4155/fmc-2018-0432 ◽

2019 ◽

Vol 11 (16) ◽

pp. 2081-2094 ◽

Cited By ~ 1

Author(s):

Tingting Guo ◽

Zhenzhong Su ◽

Qi Wang ◽

Wei Hou ◽

Junyao Li ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Western Blot ◽

Lung Inflammation ◽

Macrophage Activation ◽

Myeloperoxidase Activity ◽

Histopathological Changes ◽

Tnf Α ◽

Anti Inflammatory ◽

Inflammatory Effect

Aim: Thus far, the anti-inflammatory effect of vanillin in acute lung injury (ALI) has not been studied. This study aimed to investigate the effect of vanillin in lipopolysaccharide (LPS)-induced ALI. Results & methodology: Our study detected the anti-inflammatory effects of vanillin by ELISA and western blot, respectively. Pretreatment of mice with vanillin significantly attenuated LPS-stimulated lung histopathological changes, myeloperoxidase activity and expression levels of proinflammatory cytokines by inhibiting the phosphorylation activities of ERK1/2, p38, AKT and NF-κB p65. In addition, vanillin inhibited LPS-induced TNF-α and IL-6 expression in RAW264.7 cells via ERK1/2, p38 and NF-κB signaling. Conclusion: Vanillin can inhibit macrophage activation and lung inflammation, which suggests new insights for clinical treatment of ALI.

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P0527AROLE OF PROMOTING INFLAMMATION OF KLF6 IN ACUTE KIDNEY INURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0527a ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Dan Li ◽

Chenyu Li ◽

Yan Xu

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Cytokine ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tnf Α ◽

Public Dataset ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine ◽

Pro Inflammatory Cytokines

Abstract Background and Aims Acute kidney injury (AKI), commonly appeared in cardiac arrest, surgery and kidney transplantation which involved in ischemia-reperfusion (IR) injury of kidney. However, the mechanisms underlying inflammatory response in IR AKI is still unclear. Method Public dataset showed kruppel-like factor 6 (KLF6) was significantly highly expressed (P<0.05) in AKI, implies KLF6 might be associated with AKI. To evaluate the mechanism of KLF6 on IR AKI, 30 rats were randomly divided into sham and IR group, and were sacrificed at 0 h, 3 h, 6 h, 12 h or 24 h after IR. Results The results showed KLF6 expression was peaking at 6 h after IR, and the expression of pro-inflammatory cytokines MCP-1 and TNF-α were increased both in serum and kidney tissues after IR, while anti-inflammatory cytokine IL-10 was decreased after IR. Furthermore, in vitro results showed KLF6 knock-down reduced the pro-inflammatory cytokines expression and increased the anti-inflammatory cytokines expression. Conclusion These results suggest that (1) KLF6 might be a novel biomarker for early diagnosis of AKI and (2) targeting KLF6 expression may offer novel strategies to protect kidneys from IR AKI Figure KLF6, AKI, Control Inflammation

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Ghrelin protects mice against endotoxemia-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00044.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. F1032-F1037 ◽

Cited By ~ 56

Author(s):

Wei Wang ◽

Shweta Bansal ◽

Sandor Falk ◽

Danica Ljubanovic ◽

Robert Schrier

Keyword(s):

Acute Kidney Injury ◽

Proinflammatory Cytokines ◽

Elevated Serum ◽

Kidney Injury ◽

Serum Cytokine ◽

Renal Protection ◽

Ghrelin Receptor ◽

Tnf Α ◽

Cytokine Levels ◽

Serum Ghrelin

Acute kidney injury (AKI) in septic patients drastically increases the mortality to 50–80%. Sepsis is characterized by hemodynamic perturbations as well as overwhelming induction of proinflammatory cytokines. Since ghrelin has been shown to have anti-inflammatory properties, we hypothesized that ghrelin may afford renal protection during endotoxemia-induced AKI. Studies were conducted in a normotensive endotoxemia-induced AKI model in mice by intraperitoneal injection of 3.5 mg/kg LPS. Serum ghrelin levels were increased during endotoxemia accompanied by increased ghrelin receptor (GHSR-1a) protein expression in the kidney. Ghrelin administration (1.0 mg/kg sc 6 h and 30 min before and 14 h after LPS) significantly decreased serum cytokine levels (TNF-α, IL-1β, and IL-6) and serum endothelin-1 levels which had been induced by LPS. The elevated serum nitric oxide (NO) levels and renal inducible NO synthase expression were also decreased by ghrelin. Renal TNF-α levels were also increased significantly in response to LPS and ghrelin significantly attenuated this increase. When administrated before LPS, ghrelin protected against the fall in glomerular filtration rate at 16 h (172.9 ± 14.7 vs. 90.6 ± 15.2 μl/min, P < 0.001) and 24 h (147.2 ± 20.3 vs. 59.4 ± 20.7 μl/min, P < 0.05) as well as renal blood flow at 16 h (1.65 ± 0.07 vs. 1.47 ± 0.04 ml/min, P < 0.01) and 24 h (1.56 ± 0.08 vs. 1.22 ± 0.03 ml/min, P < 0.05) after LPS administration without affecting mean arterial pressure. Ghrelin remained renal protective even when it was given after LPS. In summary, ghrelin offered significant protection against endotoxemia-induced AKI. The renal protective effect of ghrelin was associated with an inhibition of the proinflammatory cytokines. Of particular importance was the suppression of TNF-α both in the circulation and kidney tissues. Thus, ghrelin may be a promising peptide in managing endotoxemia-induced AKI.

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Systemic and sustained thioredoxin analogue prevents acute kidney injury and its-associated distant organ damage in renal ischemia reperfusion injury mice

Scientific Reports ◽

10.1038/s41598-020-75025-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Kento Nishida ◽

Hiroshi Watanabe ◽

Masako Miyahisa ◽

Yuto Hiramoto ◽

Hiroto Nosaki ◽

...

Keyword(s):

Acute Kidney Injury ◽

Lung Injury ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Expression System ◽

Kidney Injury ◽

Renal Ischemia ◽

Tnf Α ◽

Renal Ischemia Reperfusion Injury

AbstractThe mortality of patients with acute kidney injury (AKI) remains high due to AKI associated-lung injury. An effective strategy for preventing both AKI and AKI-associated lung injury is urgently needed. Thioredoxin-1 (Trx) is a redox-active protein that possesses anti-oxidative, anti-apoptotic and anti-inflammatory properties including modulation of macrophage migration inhibitory factor (MIF), but its short half-life limits its clinical application. Therefore, we examined the preventive effect of a long-acting Trx, which is a fusion protein of albumin and Trx (HSA-Trx), against AKI and AKI-associated lung injury. Recombinant HSA-Trx was expressed using a Pichia expression system. AKI-induced lung injury mice were generated by bilateral renal ischemia reperfusion injury (IRI). HSA-Trx administration attenuated renal IRI and its-associated lung injury. Both renal and pulmonary oxidative stress were suppressed by HSA-Trx. Moreover, HSA-Trx inhibited elevations of plasma IL-6 and TNF-α level, and suppressed IL-6–CXCL1/2-mediated neutrophil infiltration into lung and TNF-α-mediated pulmonary apoptosis. Additionally, HSA-Trx suppressed renal IRI-induced MIF expression in kidney and lung. Administration of HSA-Trx resulted in a significant increase in the survival rate of renal IRI mice. Collectively, HSA-Trx could have therapeutic utility in preventing both AKI and AKI-associated lung injury as a consequence of its systemic and sustained multiple biological action.

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Interleukin-11 attenuates pulmonary inflammation and vasomotor dysfunction in endotoxin-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.5.l861 ◽

1999 ◽

Vol 277 (5) ◽

pp. L861-L867 ◽

Cited By ~ 8

Author(s):

Brett C. Sheridan ◽

Charles A. Dinarello ◽

Daniel R. Meldrum ◽

David A. Fullerton ◽

Craig H. Selzman ◽

...

Keyword(s):

Lung Injury ◽

Lung Tumor ◽

Binding Protein ◽

Saline Control ◽

Myeloperoxidase Activity ◽

Neutrophil Sequestration ◽

Tnf Α ◽

Anti Inflammatory ◽

Relaxation Responses ◽

Vasomotor Dysfunction

Interleukin (IL)-11, like other members of the gp130 receptor class, possesses anti-inflammatory properties. We hypothesized that IL-11 pretreatment would attenuate endotoxin [lipopolysaccharide (LPS)]-induced lung inflammation and diminish injury to endothelium-dependent and -independent mechanisms of pulmonary vasorelaxation that require cGMP in Sprague-Dawley rats. LPS (20 mg/kg ip) increased lung tumor necrosis factor (TNF)-α compared with the saline control (0.7 ± 0.15 ng/g lung wet wt for control vs. 3.5 ± 0.09 ng/g lung wet wt for LPS; P < 0.05). IL-11 (200 mg/kg ip) injected 10 min before LPS administration attenuated the LPS-induced lung TNF-α levels (1.6 ± 0.91 ng/g lung wet wt; P < 0.05 vs. LPS). IL-11 also diminished LPS-induced lung neutrophil sequestration as assessed by myeloperoxidase units (2.1 ± 0.25 U/g lung wet wt for saline and 15.6 ± 2.02 U/g lung wet wt for LPS vs. 7.07 ± 1.65 U/g lung wet wt for LPS plus IL-11; P < 0.05). Similarly, TNF-α binding protein (175 mg/kg) attenuated LPS-induced myeloperoxidase activity (6.04 ± 0.14 U/g lung wet wt; P < 0.05). Both IL-11 and TNF-α binding protein similarly attenuated LPS-induced endothelium-dependent vasomotor dysfunction with improved relaxation responses to 10−7and 10−6M acetylcholine and A-23187 in phenylephrine-preconstricted isolated pulmonary artery rings ( P < 0.05 vs. LPS). Endothelium-independent relaxation responses to sodium nitroprusside were also improved after LPS at 10−6M ( P < 0.05 vs. LPS). Moreover, IL-11 decreased endotoxin-induced mortality in CF1 mice from 90 to 50% ( P ≤ 0.05 vs. LPS). Therefore, IL-11 prevents LPS-induced lung TNF-α production, neutrophil sequestration, and pulmonary vasomotor dysfunction. We conclude that IL-11 possesses anti-inflammatory activity that protects against LPS-induced lung injury and lethality.

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Antecedent acute kidney injury worsens subsequent endotoxin-induced lung inflammation in a two-hit mouse model

AJP Renal Physiology ◽

10.1152/ajprenal.00194.2011 ◽

2011 ◽

Vol 301 (3) ◽

pp. F597-F604 ◽

Cited By ~ 10

Author(s):

Rajit K. Basu ◽

Emily Donaworth ◽

Derek S. Wheeler ◽

Prasad Devarajan ◽

Hector R. Wong

Keyword(s):

Acute Kidney Injury ◽

Lung Injury ◽

Lung Inflammation ◽

Kidney Injury ◽

Lavage Fluid ◽

Myeloperoxidase Activity ◽

Lung Water ◽

Monocyte Chemoattractant Protein 1 ◽

Patients At Risk ◽

Critically Ill Adults

Acute kidney injury (AKI) contributes greatly to morbidity and mortality in critically ill adults and children. Patients with AKI who subsequently develop lung injury are known to suffer worse outcomes compared with patients with lung injury alone. Isolated experimental kidney ischemia alters distal lung water balance and capillary permeability, but the effects of such an aberration on subsequent lung injury are unknown. We present a clinically relevant two-hit murine model wherein a proximal AKI through bilateral renal ischemia (30 min) is followed by a subsequent acute lung injury (ALI) via intratracheal LPS endotoxin (50 μg at 24 h after surgery). Mice demonstrated AKI by elevation of serum creatinine and renal histopathological damage. Mice with ALI and preexisting AKI had increased lung neutrophilia in bronchoalveolar lavage fluid and by myeloperoxidase activity over Sham-ALI mice. Additionally, lung histopathological damage was greater in ALI mice with preexisting AKI than Sham-ALI mice. There was uniform elevation of monocyte chemoattractant protein-1 in kidney, serum, and lung tissue in animals with both AKI and ALI over those with either injury alone. The additive lung inflammation after ALI with antecedent AKI was abrogated in MCP-1-deficient mice. Taken together, our two-hit model demonstrates that kidney injury may prime the lung for a heightened inflammatory response to subsequent injury and MCP-1 may be involved in this model of kidney-lung cross talk. The model holds clinical relevance for patients at risk of lung injury after ischemic injury to the kidney.

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Anti-Inflammatory Effects of Sosiho-Tang, a Traditional Herbal Formula, on Acute Lung Injury in LPS-Sensitized Mice and -Raw 264.7 Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6641689 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

La Yoon Choi ◽

Mi Hye Kim ◽

Da-Hwa Jung ◽

Woong Mo Yang

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Proinflammatory Cytokines ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Alveolar Wall ◽

Herbal Formula ◽

Tnf Α ◽

Ifn Γ ◽

Anti Inflammatory

Acute lung injury (ALI) is a series of syndromes with persistent inflammation and abnormally increased vascular permeability. Sosiho-tang (SSHT), a traditional herbal formula consisting of a mixture of seven herbs, has been used to treat allergic reactions and chronic hepatitis disease in East Asia. In this study, we determined whether SSHT has an inhibitory effect against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice. 0.05, 0.55, and 5.55 mg/kg of SSHT were orally administered to C57BL/6J mice for 7 days prior to the administration of LPS. After 2 h of LPS sensitization, lung tissues were collected to confirm the lung histology and ALI-related inflammatory factors. SSHT ameliorated the LPS-induced alveolar hemorrhage, alveolar wall thickening, and the shrinkage of the alveolar spaces in the ALI mice model. Proinflammatory cytokines including IL-6, TNF-α, and IFN-γ in the lung tissue were significantly regulated in the SSHT-treated groups compared to the LPS only-treated group. Also, increases of IL-6 and TNF-α and decrease of IFN-γ expressions were dose-dependently modulated by SSHT treatment in LPS-induced raw 264.7 cells. Additionally, the translocation of NF-κB into nucleus and phosphorylation of mitogen-activated protein (MAP) kinase were significantly attenuated by the treatment of SSHT in LPS-sensitized ALI mice. SSHT showed anti-inflammatory activities by inhibiting proinflammatory cytokines and NF-κB signaling in LPS-induced ALI. This study demonstrates that SSHT has preventive effects on LPS-induced ALI by regulating inflammatory responses as an alternative for treating lung diseases.

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