Combination of Pseudoephedrine and Emodin Ameliorates LPS-Induced Acute Lung Injury by Regulating Macrophage M1/M2 Polarization Through the VIP/cAMP/PKA Pathway

Abstract Background: Acute lung injury (ALI) is an acute multifactorial infectious disease induced by trauma, pneumonia, shock, and sepsis. This study aimed to investigate the protective effects of pseudoephedrine and emodin combined treatment in experimental ALI , as well as the mechanisms underlying the regulation of inflammation and pulmonary edema via the VIP /cAMP/PKA pathway.Methods: Wistar rats were divided into a control group, lipopolysaccharide(LPS) group, and a pseudoephedrine + emodin treatment group. Rats in the control group were given intraperitoneal saline injections, while rats in the LPS and treatment groups were given intraperitoneal LPS injections to induce ALI. After being treated with pseudoephedrine and emodin for 24 hours, all animals were sacrifce. Anal temperatures were taken on an hourly basis for eight hours after LPS injection. Pathological examination of lung specimen was performed by H&E staining. Cytokines (IL-1β, TNF-α, IL-6, IL-10, Arg-1, CD86, CD80, CD206, F4/80, VIP) in colon were assayed by ELISA and immunofuorescence.The expression of VIP, CAMP, AQP-1, AQP-5, p-PKA/PKA, p-IκBα/IκBα, and p-p65/p65 protein in lung was determined by western blotting.Results: After rats being treated with pseudoephedrine + emodin, the symptoms (febrility) of ALI were alleviated. The contents of infammatory cytokines (IL-1β, TNF-α, IL-6) were decreased and anti-inflammatory cytokines(IL-10, Arg-1) were signifcantly increased in serum. Pseudoephedrine + emodin treatment effectively promoted VIP cAMP and p-PKA protein expression in lung tissues, and significantly inhibited NF-κB phosphorylation,Pseudoephedrine + emodin treatment can inhibit M1 polarization and promoted M2 polarization via the VIP/cAMP/PKA signaling pathway.Conclusions: The combination of pseudoephedrine hydrochloride and emodin was effective in ameliorating LPS-induced ALI in rats by inducing VIP/cAMP/PKA signaling, inhibiting the NF-κB inflammatory pathway, suppressing macrophage M1 polarization, and promoting macrophage M2 polarization.

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Glycoproteins From Rabdosia japonica var. glaucocalyx Regulate Macrophage Polarization and Alleviate Lipopolysaccharide-Induced Acute Lung Injury in Mice via TLR4/NF-κB Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.693298 ◽

2021 ◽

Vol 12 ◽

Author(s):

An-qi Ren ◽

Hui-jun Wang ◽

Hai-yan Zhu ◽

Guan Ye ◽

Kun Li ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Western Blot ◽

Mononuclear Cells ◽

Macrophage Polarization ◽

Enzyme Linked Immunosorbent Assay ◽

Protective Effects ◽

Proinflammatory Mediators ◽

Tnf Α

Background and Aims:Rabdosia japonica var. glaucocalyx is a traditional Chinese medicine (TCM) for various inflammatory diseases. This present work aimed to investigate the protective effects of R. japonica var. glaucocalyx glycoproteins on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the potential mechanism.Methods: Glycoproteins (XPS) were isolated from R. japonica var. glaucocalyx, and homogeneous glycoprotein (XPS5-1) was purified from XPS. ANA-1 cells were used to observe the effect of glycoproteins on the secretion of inflammatory mediators by enzyme-linked immunosorbent assay (ELISA). Flow cytometry assay, immunofluorescence assay, and Western blot analysis were performed to detect macrophage polarization in vitro. The ALI model was induced by LPS via intratracheal instillation, and XPS (20, 40, and 80 mg/kg) was administered intragastrically 2 h later. The mechanisms of XPS against ALI were investigated by Western blot, ELISA, and immunohistochemistry.Results:In vitro, XPS and XPS5-1 downregulated LPS-induced proinflammatory mediators production including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and nitric oxide (NO) and upregulated LPS-induced IL-10 secretion. The LPS-stimulated macrophage polarization was also modulated from M1 to M2. In vivo, XPS maintained pulmonary histology with significantly reducing protein concentration and numbers of mononuclear cells in bronchoalveolar lavage fluid (BALF). The level of IL-10 in BALF was upregulated by XPS treatment. The level of cytokines including TNF-α, IL-1β, and IL-6 was downregulated. XPS also decreased infiltration of macrophages and polymorphonuclear leukocytes (PMNs) in lung. XPS suppressed the expression of key proteins in the TLR4/NF-κB signal pathway.Conclusion: XPS was demonstrated to be a potential agent for treating ALI. Our findings might provide evidence supporting the traditional application of R. japonica var. glaucocalyx in inflammation-linked diseases.

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Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00412.2005 ◽

2007 ◽

Vol 293 (2) ◽

pp. L446-L452 ◽

Cited By ~ 46

Author(s):

Takefumi Itoh ◽

Hiroaki Obata ◽

Shinsuke Murakami ◽

Kaoru Hamada ◽

Kenji Kangawa ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Bronchoalveolar Lavage ◽

Total Protein ◽

Intratracheal Instillation ◽

Weight Ratio ◽

Dry Weight ◽

Alveolar Wall ◽

Protective Effects ◽

Tnf Α

Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 μg·kg−1·min−1) or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-α and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis.

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Protective effects of recombinant 53-kDa protein of Trichinella spiralis on acute lung injury in mice via alleviating lung pyroptosis by promoting M2 macrophage polarization

Innate Immunity ◽

10.1177/17534259211013397 ◽

2021 ◽

pp. 175342592110133

Author(s):

Ling-yu Wei ◽

An-qi Jiang ◽

Ren Jiang ◽

Si-ying Duan ◽

Xue Xu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Trichinella Spiralis ◽

Macrophage Polarization ◽

Control Group ◽

M2 Macrophage ◽

Protective Effects ◽

Activated Macrophages ◽

Arginase 1 ◽

M2 Macrophage Polarization

Trichinella spiralis represents an effective treatment for autoimmune and inflammatory diseases. The effects of recombinant T. spiralis (TS) 53-kDa protein (rTsP53) on acute lung injury (ALI) remain unclear. Here, mice were divided randomly into a control group, LPS group, and rTsP53 + LPS group. ALI was induced in BALB/c mice by LPS (10 mg/kg) injected via the tail vein. rTsP53 (200 µl; 0.4 μg/μl) was injected subcutaneously three times at an interval of 5 d before inducing ALI in the rTsP53+LPS group. Lung pathological score, the ratio and markers of classic activated macrophages (M1) and alternatively activated macrophages (M2), cytokine profiles in alveolar lavage fluid, and pyroptosis protein expression in lung tissue were investigated. RTsP53 decreased lung pathological score. Furthermore, rTsP53 suppressed inflammation by increasing IL-4, IL-10, and IL-13. There was an increase in alveolar M2 macrophage numbers, with an increase in CD206 and arginase-1-positive cells and a decrease in alveolar M1 markers such as CD197 and iNOS. In addition, the polarization of M2 macrophages induced by rTsP53 treatment could alleviate ALI by suppressing lung pyroptosis. RTsP53 was identified as a potential agent for treating LPS-induced ALI via alleviating lung pyroptosis by promoting M2 macrophage polarization.

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Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.772031 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xin Lv ◽

Tingting Yao ◽

Rongling He ◽

Yijun He ◽

Mengyu Li ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Severe Disease ◽

Underlying Mechanism ◽

Lavage Fluid ◽

Pharmacological Therapy ◽

Protective Effects ◽

Cell Accumulation ◽

Tnf Α ◽

Anti Inflammation

Acute lung injury (ALI) is a severe disease that presents serious damage and excessive inflammation in lungs with high mortality without effective pharmacological therapy. Fluorofenidone (AKFPD) is a novel pyridone agent that has anti-fibrosis, anti-inflammation, and other pharmacological activities, while the effect of fluorofenidone on ALI is unclarified. Here, we elucidated the protective effects and underlying mechanism of fluorofenidone on lipopolysaccharide (LPS)-induced ALI. In this study, fluorofenidone alleviated lung tissue structure injury and reduced mortality, decreased the pulmonary inflammatory cell accumulation and level of inflammatory cytokines IL-1β, IL-6, and TNF-α in the bronchoalveolar lavage fluid, and attenuated pulmonary apoptosis in LPS-induced ALI mice. Moreover, fluorofenidone could block LPS-activated phosphorylation of ERK, JNK, and P38 and further inhibited the phosphorylation of IκB and P65. These results suggested that fluorofenidone can significantly contrast LPS-induced ALI through suppressing the activation of the MAPK/NF-κB signaling pathway, which indicates that fluorofenidone could be considered as a novel therapeutic candidate for ALI.

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Study on the Efficacy and Safety of Ambroxol Combined with Methylprednisolone in Patients with Acute Lung Injury

BioMed Research International ◽

10.1155/2021/5771101 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Weiwei Su ◽

Qinglian Dong ◽

Fangfang Jiao

Keyword(s):

Acute Lung Injury ◽

Treatment Group ◽

Lung Injury ◽

Oxygen Partial Pressure ◽

Partial Pressure ◽

Combined Treatment ◽

Oxygenation Index ◽

Arterial Blood Gas ◽

Arterial Blood ◽

Tnf Α

Background. There is no better treatment method towards paraquat-induced acute lung injury (ALI) at present. Ambroxol combined with methylprednisolone exhibits a significant improvement effect on ALI treatment, whereas their mechanism in ALI is still unclear. Methods. 64 patients with ALI caused by paraquat poisoning brought to our hospital from January 2015 to January 2018 were selected. They were separated into a combined treatment group (CTG) and a routine treatment group (RTG) on the basis of different treatment methods. The survival of patients was observed after 7 days of treatment. Arterial blood gas, oxygen partial pressure (PaO2), partial pressure of carbon dioxide (PaCO2), oxygenation index (PaO2/FiO2), patient’s spontaneous respiratory rate (RR), tidal volume (VT), and positive end-expiratory pressure (PEEP) were observed before and after treatment for 7 days. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were analyzed. The differences of indexes between the dead patients and the survivors were observed, and the potential predictive value of death was analyzed. Results. After treatment, the indexes of patients were significantly improved in both groups compared with those before therapy. Further comparison showed that the improvement of PaO2, PaCO2, and PaO2/FiO2 in CTG was obviously higher than that in RTG ( p < 0.05 ). The improvement of RR, PEEP, and VT in CTG was obviously higher than that in RTG ( p < 0.05 ). The decreased degree of IL-6 and TNF-α in CTG was higher than that in RTG ( p < 0.05 ). The 7-day mortality rate of 64 patients was 39.06%, and there was no obvious difference in the 7-day survival rate in both groups ( p = 0.649 ). IL-6 and TNF-α were expected to be potential prediction indexes of paraquat-induced ALI. Conclusion. Ambroxol combined with methylprednisolone significantly improved the oxygen partial pressure and oxygenation index of patients with paraquat-induced ALI and inhibited the inflammatory response of patients.

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The Role of Vagus Nerve on Dexmedetomidine Induced Survival and Lung Protection in a Sepsis Model in Rats.

10.21203/rs.3.rs-483367/v1 ◽

2021 ◽

Author(s):

Yumo Li ◽

Binbin Wu ◽

Cong Hu ◽

Jie Hu ◽

Qingquan Lian ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Vagus Nerve ◽

Vagal Nerve ◽

Lung Injury Score ◽

Enzyme Linked Immunosorbent Assay ◽

Protective Effects ◽

Lung Protection ◽

Tnf Α

Abstract BackgroundSepsis often results in acute lung injury (ALI). Sedative dexmedetomidine (Dex) was reported to protect cells and organs due to its direct cellular effects. This study aims to investigate the role of vagus nerves on Dex induced lung protection in a model of lipopolysaccharide (LPS)-induced ALI in rats. MethodsThe bilateral cervical vagus nerve of male Sprague-Dawley rats was sectioned or just exposed without section as sham surgery. The ALI was induced by intraperitoneal injection of LPS (1 or 10 mg/kg). After LPS administration, Dex antagonist yohimbine (YOH) (1 mg/kg) and/or Dex (25 μg/kg) was injected intraperitoneally at 0, 4, 8 and 12 hours to rats with or without vagotomy. The severity of ALI was determined with survival curve analysis and lung pathological scores of haematoxylin and eosin (H-E) staining sections. The plasma concentrations of interleukin 1beta (IL-1β), tumour necrosis factor-alpha (TNF-α), catecholamine (CA) and acetylcholine (Ach) were measured with enzyme-linked immunosorbent assay (ELISA). ResultsThe median survival time of LPS-induced ALI rats was significantly prolonged by Dex (22 hours, 50% CI, [31.25, 90.63]) compared that in the LPS group (14 hours, 50% CI, [18.75, 81.25], P < 0.05), and the acute lung injury score was significantly reduced by Dex (6.5, 50% CI, [5.75, 7.5] vs 11.5, 50% CI, [10.75, 12.50] in the LPS group, P < 0.01). However, these protective effects of Dex were significantly reduced by either YOH administration or vagotomy. Dex significantly decreased LPS-induced plasma IL-1β (pg/ml) (20.75 ± 0.78 vs. 30.22 ± 2.62, P < 0.01), TNF-α (pg/ml) (205.30 ± 9.39 vs. 273.40 ± 14.50, P < 0.01), and CA (pg/ml) (825.70 ± 43.46 vs. 1188.00 ± 64.40, P < 0.01) but increased the secretion of Ach (pg/ml) (507.20 ± 49.52 vs. 296.50 ± 62.44, P < 0.01); these effects of Dex was partially abolished by vagotomy. ConclusionsOur data suggested that Dex increased vagal nerve tone which partially contributed to its anti-inflammatory and lung protective effects. The indirect anti-inflammation and direct cytoprotection of Dex are likely through high vagal nerve tone and α 2 -adrenoceptor activation, respectively.

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Phillygenin attenuates LPS-induced acute lung injury of newborn mice in infantile pneumonia

10.22514/sv.2021.085 ◽

2021 ◽

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Lung Tissue ◽

Control Group ◽

Western Blot Assay ◽

Newborn Mice ◽

Cell Counts ◽

Tnf Α ◽

Underlying Mechanisms ◽

And Control

Purpose: The aim of this study was to assess the effect of phillygenin (PHI) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and understand its underlying mechanisms. Methods: Mice were separated into four different groups at random, including LPS, LPS+ PHI (5 mg/kg), LPS + PHI (50 mg/kg) and control group. The two LPS + PHI groups were intraperitoneally administered with PHI after LPS intratracheal administered for 1 h. Subsequently, the lung tissues of different groups were collected and evaluated by H&E staining and W/D (W/D) ratio. The inflammatory cytokines in BALF or lung tissue were also assessed. Western blot assay was applied to examine the expressions of TLR4, MyD88, and NF-κB. Results: The ameliorated pathological changes and lung W/D ratio demonstrated that PHI dramatically suppressed the lung injury levels. PHI strikingly reduced the number of inflammatory cell counts and total protein concentration in BALF. In addition, PHI attenuated expression of IL-1β and TNF-α in BALF and lung tissue. Furthermore, it was confirmed that PHI alleviated LPS-induced ALI via TLR4/MyD88/NF-κB pathway. Conclusions: Together the above results show that PHI attenuates LPS-induced ALI via inactivation of TLR4/MyD88/NF-κB pathway in newborn mice.

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Basic research on the effects of hyperbaric oxygen combined with hydrogen-rich saline on acute lung injury induced by lipopolysaccharide

10.21203/rs.3.rs-142869/v1 ◽

2021 ◽

Author(s):

Yintao Chang ◽

Zhenzhen Zhang ◽

Xiaochen Bao ◽

Mingdong Wang ◽

Yuxiang Jin ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Hyperbaric Oxygen ◽

Cell Apoptosis ◽

Combined Treatment ◽

Weight Ratio ◽

Inflammatory Factors ◽

Control Group ◽

Therapeutic Effects ◽

Pulmonary Tissue

Abstract Background To investigate the effects of hydrogen-rich saline (HRS) combined with hyperbaric oxygen (HBO) on acute lung injury (ALI) and its clinical significance. Methods 40 adult male Sprague-Dawlay rats were randomly divided into 5 groups: the sham, LPS, LPS + HBO, LPS + HRS and LPS + HBO + HRS. LPS at a rate of 3 mg/kg was injected into the trachea of the experimental animals to develop ALI model, then the animals were respectively given simple HBO or HRS treatment or combined treatment. 3 days later, we study lung pathological, the levels of inflammatory factors, and cell apoptosis in the pulmonary tissue was detected by Tunel and cell apoptosis rate was calculated accordingly. Results In the groups treated with HRS and HBO, pulmonary pathological data, wet-dry weight ratio and immflammatory factors in the pulmonary tissues and avelar lavage fluid were signficantly superiror to those of the control group(P < 0.05). Cell apoptosis detection revealed that treatment with either simple HRS and HBO or combined treatment of the two could all alleviate cell apoptosis, and the combined treatment with HRS and HBO was obviously superior to single treatment༈P < 0.05༉. Conclusions HRS and HBO could all decrease the release of immflammatory cytokines in lung tissue, reduce accumulation of oxidative products and alleviate apoptosis of pulmoanry cells, and could produce good therapeutic effects on ALI induced by LPS. HBO combined with HRS seems to have a synergistic effect on the decrease of cell apoptosis, and in the expression of immflammatory cytokines and the generation of related immflammatory products, the combined use of HBO and HRS showed a decreasing trend as compared with simple application.

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Protectin conjugates in tissue regeneration 1 restores lipopolysaccharide-induced pulmonary endothelial glycocalyx loss via ALX/SIRT1/NF-kappa B axis

Respiratory Research ◽

10.1186/s12931-021-01793-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Xin-Yang Wang ◽

Xin-Yu Li ◽

Cheng-Hua Wu ◽

Yu Hao ◽

Pan-Han Fu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Cytokines ◽

Tissue Regeneration ◽

Umbilical Vein ◽

Endothelial Glycocalyx ◽

Lipid Mediator ◽

Protective Effects ◽

Pulmonary Vascular Permeability

Abstract Background Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. Methods PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. Results In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. Conclusion PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.

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