Folic Acid Supplementation Reversed Lung Inflammatory Response, Oxidative Damage and Histopathological Alterations in an LPS-Induced Rat Model of Lung Injury

Alpha glucocorticoid receptor expression in different experimental rat models of acute lung injury

The present study focused on the therapeutic effects of resveratrol in a rat model of blunt chest trauma-induced acute lung injury and the potential role of endocan as a biomarker of inflammation. They were randomly divided into the following four groups (n=7 in each group): control group (no treatment or trauma); trauma group (trauma-induced group); resveratrol group (resveratrol [0.3mg/kg] administered via the i.p. route group); and resveratrol + trauma group (resveratrol [0.3mg/kg] administered via the i.p. route 1h prior to the induction of trauma At the end of the 24h, all the experimental rats were sacrificed. Lung lobe and blood samples were collected for biochemical, histopathological, and immunohistochemical investigations. Serum endocan levels were found to be significantly higher in the travma, resveratrol, and resveratrol + trauma groups than in the control group (p<0.001, p<0.001, p<0.001). Moreover, in resveratrol + trauma group, endocan showed a significant increase compared to trauma and resveratrol group (p<0.001, p<0.001). Serum MDA level was significantly higher in the trauma group than in the control group (p=0.017). SOD showed a significant increase in resveratrol and resveratrol + trauma groups compared to control group (p<0.001, p<0.001). The present study suggested that resveratrol exerted antioxidant properties in a rat model of lung injury after blunt chest trauma. Thus, it may have therapeutic potential in cases of blunt chest trauma-induced lung injury. Serum levels of endocan were not correlated with the inflammation response. The clinical use of endocan as a biomarker of inflammation in lung injury caused by blunt chest trauma is not recommended.

Hypoxia can induce lung injury such as pulmonary arterial hypertension and pulmonary edema. And in the rat model of hypoxia-induced lung injury, the expression of Farnesyl diphosphate farnesyl transferase 1 (Fdft 1) was highly expressed and the steroid biosynthesis pathway was activated. However, the role of Fdft 1 and steroid biosynthesis pathway in hypoxia-induced lung injury remains unclear. The study aimed to further investigate the relationship between Fdft1 and steroid biosynthesis pathway with hypoxia-induced lung injury. A rat model of lung injury was constructed by hypobaric chamber with hypoxic stress, the adenovirus interference vector was used to silence the expression of Fdft 1, and the exogenous steroid biosynthesis metabolite Vitamin D3 (VD3) was used to treat acute hypoxia-induced lung injury in rats. Sh-Fdft 1 and exogenous VD3 significantly inhibited the expression of Fdft 1 and the activation of the steroid pathway in hypoxia-induced lung injury rats, which showed a synergistic effect on the steroid activation pathway. In addition, sh-Fdft 1 promoted the increase of pulmonary artery pressure and lung water content, the decrease of oxygen partial pressure and oxygen saturation, and leaded to the increase of lung cell apoptosis and the aggravation of mitochondrial damage in hypoxia-stressed rats. And VD3 could significantly improve the lung injury induced by hypoxia and sh-Fdft 1 in rats. Fdft 1 gene silencing can promote hypoxic-induced lung injury, and exogenous supplement of VD3 has an antagonistic effect on lung injury induced by Fdft 1 gene silencing and hypoxic in rats, suggesting that VD3 has a preventive and protective effect on the occurrence and development of hypoxia-induced lung injury.

BackgroundThis study aimed to investigate the effects of dexmedetomidine in a rat model of sepsis-induced lung injury and the role of the adenosine monophosphate-activated protein kinase (AMPK) gene and silent information regulator 1 (SIRT1) gene signaling pathway.Material/MethodsSixty 28-week-old healthy male Sprague-Dawley rats were randomly divided into three groups, the sham group, the model group, and the dexmedetomidine-treated group. The rat model of sepsis-induced lung injury was developed by surgical cecal ligation and puncture. Lung tissues examined histologically in the three study groups. Cell apoptosis was measured using the TUNEL assay, and the expression of inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-10 were measured in rat lung tissue by enzyme-linked immunosorbent assay (ELISA). Apoptosis-associated proteins and AMPK/SIRT1 pathway-associated protein expression levels were detected using Western blot.ResultsDexmedetomidine significantly increased the survival rate and reduced the body temperature of rats in the model group with sepsis-induced lung injury, reduced lung injury, significantly reduced apoptosis in lung tissues, and reduced the expression levels of TNF-α, and IL-1β, and increased the levels of IL-10. Dexmedetomidine significantly reduced the expression of caspase-3 in the rat lung tissue (P<0.01), and significantly increased the expression of Bcl-2/Bax and the phosphorylation levels of AMPK, SIRT1, nuclear factor-κB (NF-κB), and forkhead box class O 3a (FOXO3a).ConclusionsIn a rat model of sepsis-induced lung injury, dexmedetomidine reduced lung damage by activating the AMPK/SIRT1 signaling pathway and reduced the expression of inflammatory cytokines and cell apoptosis.

This research explored the protective role and underlying mechanism of Shenfu Injection (SFI) in a rat model of sepsis-induced acute lung injury (ALI), with particular attention to the modulation of the receptor-interacting protein kinase 3 (RIPK3) signaling pathway. A rat model of sepsis-induced acute lung injury (ALI) was generated through the cecal ligation and puncture (CLP) procedure. Animals were randomly assigned to four groups: Sham, CLP, CLP+SFI (10 mL/kg, intraperitoneal), and CLP+SFI high-dose (20 mL/kg). After 24 hours, lung and serum samples were collected. Histopathological alterations in pulmonary tissues were examined using hematoxylin-eosin (H&amp;E) staining and evaluated by lung injury scoring. The wet-to-dry (W/D) ratio was calculated to assess pulmonary edema. Serum concentrations of TNF-α and IL-6 were quantified by ELISA. Expression levels of RIPK3 and mixed lineage kinase domain-like protein (MLKL) in lung tissues were analyzed through Western blotting and immunohistochemistry. Relative to the CLP group, Shenfu Injection (SFI) treatment notably mitigated alveolar structural impairment, suppressed inflammatory cell infiltration, and lowered lung injury scores. SFI administration also markedly reduced the pulmonary wet-to-dry (W/D) ratio and serum concentrations of TNF-α and IL-6. Western blotting revealed that the CLP group exhibited elevated expression of RIPK3 and phosphorylated MLKL, whereas these proteins were significantly diminished in rats receiving SFI. Shenfu Injection (SFI) alleviates sepsis-induced acute lung injury in rats through the suppression of inflammatory responses and the inhibition of RIPK3/MLKL-dependent necroptotic signaling. These results indicate that regulation of the RIPK3 pathway could represent a key mechanism contributing to the protective action of SFI against sepsis-related organ damage.

Introduction: Sepsis is a mayor cause of acute respiratory distress syndrome (ARDS). In sepsis, the anticoagulant system is impaired. Nebulization of anticoagulants might allow for higher pulmonary concentration and reduce the risk of systemic bleeding. Objectives: To assess the effects of nebulized heparin in a rat model of acute lung injury. Methods: Adult male Sprague-Dawley rats (250-300 g; n=8/group) were subjected to intratracheal administration (IA) of LPS (10 μg/g b.w.). Saline or heparin (1000 IU/kg) were nebulized at 4 and 8h after LPS instillation. Animals were sacrificed 24h after the injury. Inflammatory cells and total proteins were assessed in bronchoalveaolar lavage fluid (BALF). IL-6, GROKC and TNFA were measured in lung homogenate by multiplex assay. Data are reported as mean±SD. One-way ANOVA was used for multigroup comparisons. Results: In BALF, nebulized heparin significantly reduced neutrophils in animals instilled with LPS (12±4x107 cells/ml) compared to animals administrated with LPS and nebulized with saline (18±6x107 cells/ml, p<0.05). Total BALF proteins were found to be lower in rats nebulized with heparin (578±89μg/ml) than in rats treated with saline (914±250μg/ml, p<0.005). In lung homogenate, IL-6, TNF-α, GRO-κC levels significantly decreased in animals nebulized with heparin compared to those ones nebulized with saline (IL6: LPS+Sal: 147±1ng/ml, LPS+Hep: 47±20, p<0.005; TNF-α: LPS+Sal: 1.1±0.2 ng/ml, LPS+Hep: 0.3±0.1, p<0.005; GRO-κC: LPS+Sal: 45±22ng/ml, LPS+Hep: 40±9, p<0.005). Conclusions: Our results showed that nebulized heparin administration reduced pulmonary inflammatory response in a rat model of acute lung injury.

Impact of air blast overpressure waves (OPW), or shock wave, with the body wall or body armor produces two types of energy waves: high-frequency low-amplitude stress waves and long-duration low-frequency share waves. These types of energy waves are characterized by different mechanisms of primary tissue injury that mostly affect lung. Systemic inflammation and resultant acute respiratory distress syndrome are known major secondary causative agents of delayed multiple organ failure and subsequent death after OPW exposure. However, association of each pattern of the blast OPW-produced energy waves with postexposure inflammatory events has not yet been delineated. The objectives of the present research were a) establishment of a rat model for assessment of the inflammatory response following lung injury produced by exposure to medium-amplitude (approximately 120 kPa) low-frequency (260+/-5 Hz) OPWs; and b) assessment of the dynamics of alteration in polymorphonuclear leukocyte counts and expression of CD11b adhesion molecules on the surface of polymorphonuclear leukocytes and status of iron-transferrin complexes in peripheral blood after OPW exposure. This study focused on the OPW effects at different time periods, using a sequential approach to postexposure events. Lung injury in rat was induced by OPW generated in a laboratory shock tube. Animals were exposed to OPW (at peak overpressure of 118+/-7 kPa) that produced "moderate" lung injury. Military research institute. Twenty-seven CVF Sprague-Dawley rats were subjected to OPW exposures, and 17 sham-treated animals were used as control. Lung tissue and blood samples were collected at 1, 3, 6, 12, and 24 hrs following OPW exposures and compared with samples collected from nonexposed animals. OPW-induced lung injury caused a 2.7-fold increase in the number of circulatory polymorphonuclear leukocytes as early as 1 hr postexposure, which is indicative of mobilization of the pool of marginated polymorphonuclear leukocytes into the free circulation. Polymorphonuclear leukocyte counts increased through the following 3- and 6-hr periods, when they were, respectively, 5-fold and 3.5-fold higher than in controls. These effects were accompanied by a pronounced expression of CD11b in polymorphonuclear leukocytes and tissue sequestration of blood iron-transferrin complexes during the entire 24-hr period of observations. The increase in circulatory polymorphonuclear leukocytes was accompanied by a decrease in iron-transferrin complex concentrations that apparently reflected implication of blood plasma iron in the inflammatory cell response to OPW-induced injury. The observed dynamics in polymorphonuclear leukocyte alterations in peripheral blood after OPW exposure were similar to those found recently in clinical observations of nonpenetrating injury and in animal models of infectious insults. Therefore, our data suggest that the main pattern of proinflammatory alterations in the rat model of lung injury induced by exposure to long-duration shock wave is similar to patterns that are characteristic of major trauma. The data further suggest that the expression of polymorphonuclear leukocyte CD11b and the response of iron-transferrin complex can be considered as potential surrogate markers in blood for systemic alterations following OPW-induced injury and, therefore, warrant further investigation in a human pilot study.

Effects of nebulized antithrombin and heparin on inflammatory and coagulation alterations in an acute lung injury model in rats

Irradiation of Varying Volumes of Rat Lung to Same Mean Lung Dose: a Little to a Lot or a Lot to a Little?

Methylprednisolone effects on oxygenation and histology in a rat model of acute lung injury

Purpose: To study the effect of different doses of dexmedetomidine on lung function and lung tissue cell apoptosis in a rat model of hyperoxic acute lung injury.&#x0D; Methods: Five groups of healthy male Sprague-Dawley rats were used: normal rats, untreated hyperoxic rats, and hyperoxic rats given 3 different doses of dexmedetomidine, with 20 rats in each group. The levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined usingenzyme-linked immunosorbent assay (ELISA). Parietal paraffin cuts were taken from the right upper lobe for measurement of apoptosis using in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and the apoptosis index was calculated.&#x0D; Results: At 24 and 48 h, the levels of IL-6 and TNF-α in the hyperoxia model group were significantly higher than those in the normal control group, and their levels in the middle- and high-dose groups were markedly lowered, relative to untreated hyperoxia rats (p &lt; 0.05). Apoptosis index in the hyperoxia model rats significantly increased, relative to normal rats (p &lt; 0.05). The apoptosis index in the mediumand high-dose groups decreased significantly (p &lt; 0.05).&#x0D; Conclusion: Dexmedetomidine inhibits inflammatory responses caused by high concentration of oxygen inhalation, minimizes lung injury, improves lung function and inhibits lung apoptosis.&#x0D; Keywords: Dexmedetomidine, Hyperoxia, Acute lung injury, Lung function, Apoptosis

Sepsis is a serious clinical condition resulting from severe infection. High rates of mortality and tissue damage have been reported in intensive care unit (ICU) patients with sepsis. Bovine lactoferrin (BLF) is a well-known 80-kDa glycoprotein in the transferrin family that inhibits sepsis in low-birth-weight neonates. The present study investigated the protective effects of BLF in a rat model of sepsis-induced acute lung injury (ALI). The wet/dry ratio, lipid peroxidation, antioxidant markers, total protein, total cell count, inflammatory markers and myeloperoxidase (MPO) levels were assessed. Histopathological analysis was also carried out. BLF treatment reduced the wet/dry ratio of lung tissue by 30.7% and 61.3%, and lipid peroxidation by 22.3% and 67%, at concentrations of 100 and 200 mg/kg, respectively. Superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (Gpx) and catalase were increased by more than 50% under treatment with 200 mg/kg BLF. Inflammatory markers, neutrophils, lymphocytes and total cell count were reduced by more than 50% under treatment with 200 mg/kg BLF. BLF treatment significantly reduced MPO activity, by 28.2% and 74.3%, at concentrations of 100 and 200 mg/kg, respectively. Neutrophilic infiltration and edema were observed in control rats. However, BLF treatment restored intestinal microvilli to the normal range and reduced inflammatory cell invasion. Collectively, these results suggest that BLF is an effective therapeutic agent against sepsis-induced ALI.

Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain leading factors for morbidity and mortality in critically ill patients. A significant aspect of ALI and ARDS is impaired alveolar fluid clearance (AFC). Improvements in therapies for these types of respiratory illnesses will require an understanding of the mechanisms that control AFC. The present study was designed to determine whether the administration of dobutamine decreases pulmonary edema and stimulates AFC in a rat model of lipopolysaccharide-induced lung injury. Adult male Sprague-Dawley rats were randomly divided into three groups: control, lipopolysaccharide, and lipopolysaccharide + dobutamine. The effect of dobutamine on AFC and the expression of aquaporin-1 and aquaporin-5 were examined. Lipopolysaccharide administration results in significant lung injury with impaired AFC, while dobutamine improves alveolar fluid reabsorption with elevation of aquaporin-1 and aquaporin-5. Our study indicates that dobutamine may enhance alveolar fluid reabsorption by increasing the expression of aquaporin-1 and aquaporin-5.

The aim of this study was to investigate whether or not peiminine inhibits lung inflammation and pulmonary fibrosis in a rat model of bleomycin-induced lung injury. Rats were randomly divided into 4 groups. In 3 groups, intratracheal bleomycin (5 mg/kg) was used to induce acute lung injury, followed by administration of either carboxymethyl cellulose (control group, n=14), dexamethasone (DXS group, n=14) or peiminine (peiminine group, n=10). In the fourth group (sham-operated, n=12), normal saline was instilled instead of bleomycin, followed by administration of carboxymethyl cellulose. Drugs were administered intragastrically for 28 days. Lung sections were stained with hematoxylin and eosin (H&E) and Masson's trichrome, to grade the degree of alveolitis and pulmonary fibrosis. The lung index was calculated as the ratio of lung to body weight. Serum levels of interleukin-4 (IL-4), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were obtained using a radioimmunoassay. Immunocytochemical methods were employed to assess the expression of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), NF-κB, extracellular signal-related kinase (ERK1/2), Fas and FasL in lung tissue. Peiminine and DXS significantly reduced alveolar inflammation and pulmonary interstitial inflammation in rats with bleomycin-induced lung injury. These protective effects were associated with significant (P<0.05) decreases in the levels of IFN-γ in serum and of TGF-β, CTGF, ERK1/2, NF-κB and FasL in lung tissue. No effects were observed on serum TNF-α or IL-4. In conclusion, peiminine inhibits lung inflammation and pulmonary fibrosis in a rat model of bleomycin-induced lung injury, by reducing circulating IFN-γ levels and inhibiting signal transduction pathways involving TGF-β, CTGF, ERK1/2, NF-κB and FasL.

The aim of this study was to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) and matrix metalloproteinase-9 (MMP-9) on alveolar-capillary barrier disruption and lung edema in rat models of severe acute pancreatitis-associated lung injury (PALI). A total of 40 male Sprague-Dawley rats were randomly divided into a sham surgery group (n=10) and three PALI groups, in which acute pancreatitis was induced by the retrograde infusion of 5% sodium taurocholate (1 ml/kg). The PALI groups were as follows: i) Untreated PALI group (n=10); ii) 2-methoxyestradiol (2ME2) group (5 mg/kg body mass; n=10); and iii) 2ME2 group (15 mg/kg body mass; n=10). In the two 2ME2 groups, the HIF-1α inhibitor 2ME2 was administered intraperitoneally 1 h after the induction of AP. The severity of the pancreatitis was evaluated by the serum amylase levels and pathology. The severity of the lung injury was evaluated by the wet/dry ratio, blood gas analysis and pathology. The alveolar-capillary barrier disruption was assessed by Evans blue dye extravasation. The protein and mRNA expression levels of HIF-1α and MMP-9 were studied using enzyme-linked immunosorbent assays (ELISAs), western blot analysis and reverse transcription-polymerase chain reaction. The active tumor necrosis factor-α levels were measured using an ELISA. The HIF-1α inhibitor 2ME2 attenuated the severity of the pancreatitis and PALI, while the lung edema and alveolar-capillary barrier disruption were significantly ameliorated compared with those in the untreated PALI group. Administration of the higher dose of 2ME2 significantly suppressed the protein expression of MMP-9 in the lung tissues. The results indicate that HIF-1α has a major function in alveolar-capillary barrier disruption and lung edema in PALI via a molecular pathway cascade involving MMP-9. Inhibition of HIF-1α by 2ME2 attenuates alveolar-capillary barrier disruption and lung edema. Pharmacological blockade of this pathway in patients with PALI may provide a novel therapeutic strategy.