Postconditioning with α7nAChR Agonist Attenuates Systemic Inflammatory Response to Myocardial Ischemia–Reperfusion Injury in Rats

The inflammatory response plays a major role in ischemia-reperfusion injury (IRI). Considering that cholinergic stimulation can inhibit inflammatory response through the cholinergic anti-inflammatory pathway (CAP) and the α subunit-containing nicotinic acetylcholine receptor(α7nAChR) expressed by immune cells is an important component of CAP, we assessed the effect of postconditioning with α7nAChR agonist on systemic inflammatory response during the myocardial ischemia-reperfusion process in an in vivo rat model. Thirty Sprague Dawley rats were randomly divided into three groups: sham group, control group, and postconditioning with α7nAChR agonist group (PP group). In the groups other than the sham group, the left anterior descending coronary artery was ligated for 30 min followed by a 180-min reperfusion. At the end of the experiment, the serum levels of troponin I, tumor necrosis factor α, interleukin-6, and high-mobility group box 1 were assayed, and the infarct size was assessed. The results showed that postconditioning with α7nAChR agonist significantly attenuated the systemic inflammatory response to myocardial IRI, as evidenced by decreased serum levels of tumor necrosis factor α and high-mobility group box 1. Also, this treatment protected against myocardial IRI, as shown by reduced infarct size and serum troponin I level.     

Role of Scutellarin in Ameliorating Lung Injury in a Rat Model of Bilateral Hind Limb Ischemia–Reperfusion

The lung is one of the most sensitive organs that are vulnerable to injuries induced by lower limb ischemia–reperfusion. Scutellarin is a flavonoid glycoside extracted from the Chinese herb Erigeron breviscapus. This study aimed to investigate the role of scutellarin in ameliorating lung injury in a rat model of bilateral hind limb ischemia–reperfusion. Twenty-four adult male albino rats were equally divided into four groups; control, scutellarin, bilateral hind limb ischemia–reperfusion, and bilateral hind limb ischemia–reperfusion followed by scutellarin (at a dose of 20 mg/kg/day for 14 days). Lung specimens were processed for different biochemical and histological techniques. The bilateral hind limb ischemia–reperfusion group showed a significant increase in lung malondialdehyde and myeloperoxidase levels as well as a significant decrease in lung glutathione and superoxide dismutase. Histological examination revealed collapsed alveoli, polymorphic mononuclear cell infiltration, thickened dilated congested blood vessels, and excessive collagen fiber deposition in thickened interalveolar septa. A significant increase in iNOS and Bax immunohistochemical expression was associated with a significant decrease in Bcl2 and COX2 expression. Scutellarin administration following bilateral hind limb ischemia–reperfusion significantly ameliorated all studied parameters. It can be concluded that scutellarin could be beneficial in improving bilateral hind limb ischemia–reperfusion-induced lung damage most probably through its antioxidant, anti-inflammatory, and antiapoptotic effects. Anat Rec, 302:2070–2081, 2019. © 2019 American Association for Anatomy     

Fisetin Alleviates Lipopolysaccharide-Induced Acute Lung Injury via TLR4-Mediated NF-κB Signaling Pathway in Rats

Acute lung injury (ALI), a common component of systemic inflammatory disease, is a life-threatening condition without many effective treatments. Fisetin, a natural flavonoid from fruits and vegetables, was reported to have wide pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. The aim of this study was to detect the effects of fisetin on lipopolysaccharide (LPS)-induced acute lung injury and investigate the potential mechanism. Fisetin was injected (1, 2, and 4 mg/kg, i.v.) 30 min before LPS administration (5 mg/kg, i.v.). Our results showed that fisetin effectively reduced the inflammatory cytokine release and total protein in bronchoalveolar lavage fluids (BALF), decreased the lung wet/dry ratios, and obviously improved the pulmonary histology in LPS-induced ALI. Furthermore, fisetin inhibited LPS-induced increases of neutrophils and macrophage infiltration and attenuated MPO activity in lung tissues. Additionally, fisetin could significantly inhibit the Toll-like receptor 4 (TLR4) expression and the activation of NF-κB in lung tissues. Our data indicates that fisetin has a protective effect against LPS-induced ALI via suppression of TLR4-mediated NF-κB signaling pathways, and fisetin may be a promising candidate for LPS-induced ALI treatment.     

Effect of Moderate Hypothermia on the Expression of ICAM-1 in Rat Acute Lung Injury

Clinical and experimental studies have provided that anearly event in the development of acute lung injury (ALI)is the accumulation and activation of neutrophils in thelung. The up regulation of intercellular adhesion moleculesis required fo…     

Epidermal Growth Factor Promotes Proliferation and Improves Restoration After Intestinal Ischemia–Reperfusion Injury in Rats

Epidermal growth factor (EGF) is an attractive and promising therapeutic application for intestinal disorders. The current study examined its influence on proliferation and restoration after ischemia–reperfusion (I/R) injury in rat small intestine. Six groups were performed: sham operation (Con); ischemia for 30 min with subsequent reperfusion for 30 min (I/R); I/R injured with 500 μg/kg EGF injected 5 min before ischemia (Pre-l); I/R injured with 50 μg/kg EGF injected 5 min before ischemia (Pre-s); I/R injured with 500 μg/kg EGF injected 5 min after reperfusion (Post-l); and I/R injured with 50 μg/kg EGF injected 5 min after reperfusion (Post-s). Intestinal histological damage, crypt cell proliferation degree, mucosal permeability, tight junction proteins expression, and levels of inflammation factors were studied for each group. Compared with the I/R group, administration of EGF in the Pre-l, Pre-s, and Post-l groups all presented a significant proliferation effect. The levels of FD4, IL-6, and TNF-α were dramatically decreased in all EGF-treated groups. Histological destruction was improved and TJs recovery was notably accelerated in all EGF-treated groups except the Post-s group. d-lactate concentration was only diminished in the Pre-l group. These results suggest that mucosally applied EGF can promote intestinal proliferation and improve restoration after I/R injury. EGF intraluminal administration is an effective treatment against intestinal I/R injury.     

Role of the Urokinase-Fibrinolytic System in Epithelial–Mesenchymal Transition during Lung Injury

Alveolar type II epithelial (ATII) cell injury precedes development of pulmonary fibrosis. Mice lacking urokinase-type plasminogen activator (uPA) are highly susceptible, whereas those deficient in plasminogen activator inhibitor (PAI-1) are resistant to lung injury and pulmonary fibrosis. Epithelial–mesenchymal transition (EMT) has been considered, at least in part, as a source of myofibroblast formation during fibrogenesis. However, the contribution of altered expression of major components of the uPA system on ATII cell EMT during lung injury is not well understood. To investigate whether changes in uPA and PAI-1 by ATII cells contribute to EMT, ATII cells from patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, and mice with bleomycin-, transforming growth factor β–, or passive cigarette smoke–induced lung injury were analyzed for uPA, PAI-1, and EMT markers. We found reduced expression of E-cadherin and zona occludens-1, whereas collagen-I and α-smooth muscle actin were increased in ATII cells isolated from injured lungs. These changes were associated with a parallel increase in PAI-1 and reduced uPA expression. Further, inhibition of Src kinase activity using caveolin-1 scaffolding domain peptide suppressed bleomycin-, transforming growth factor β–, or passive cigarette smoke–induced EMT and restored uPA expression while suppressing PAI-1. These studies show that induction of PAI-1 and inhibition of uPA during fibrosing lung injury lead to EMT in ATII cells.Idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases are characterized by destruction of lung architecture due to excessive deposition of extracellular matrix proteins by activated fibroblasts or myofibroblasts, leading to progressive dyspnea and loss of lung function.^1–3 The origins of myofibroblasts participating in the pathological remodeling of IPF lungs are not clear. Histopathological evaluation demonstrates that myofibroblasts accumulate in fibroblastic foci. Emerging evidence suggests that polarized type II alveolar epithelial (ATII) cells undergo epithelial–mesenchymal transitions (EMT) after lung injury. The ATII cells assume phenotypic changes such as increased migration, invasion, resistance to apoptosis, and production of elevated levels of extracellular matrix proteins^4,5 and therefore serve as a source of myofibroblasts. Understanding the possible mechanisms contributing to EMT in ATII cells may help identify new targets to treat or at least limit fibrogenesis after lung injury.A number of molecular processes are involved in the initiation of EMT in ATII cells.⁵ Components of the fibrinolytic system such as urokinase-type plasminogen activator (uPA), uPA plasma membrane receptor (uPAR), and its major inhibitor, plasminogen activator inhibitor (PAI-1) are all elaborated by ATII cells. These proteins independently influence a broad range of biological processes germane to lung injury and its repair.⁶ However, their role in fibrogenesis via EMT is unclear. Recent publications using bleomycin (BLM)⁷ and a passive cigarette smoke (PCS)⁸ or adenovirus expressing constitutively active transforming growth factor β (Ad-TGF-β)^1,9 exposure model of lung injury indicate that a coordinate increase in PAI-1 and a decrement in uPA by ATII cells promote lung injury and subsequent pulmonary fibrosis (PF). We also found that caveolin-1 scaffolding domain peptide (CSP) acts as a competitor to caveolin-1, restores expression of uPA and uPAR, and inhibits PAI-1 in ATII cells after lung injury. These changes prevent development of PF after lung injury.⁷ Recent literature suggests that up to 30% to 50% of myofibroblasts may be derived via EMT during fibrogenesis.^10–12 However, an in vivo genetic lineage tracing study reported by Rock et al¹³ contradicts these findings. Our objective in the current study is to elucidate the role of altered expression of uPA, uPAR, and PAI-1 after lung injury in EMT, and further evaluate whether reinstatement of baseline expression of uPA, uPAR, and PAI-1 by CSP intervention after lung injury reduces EMT in ATII cells.     

Hepatocellular Calcification in Severe Ischemia–Reperfusion Injury in a Liver Allograft

Ischemia–reperfusion injury (IR) of solid organ allografts is a consequence of ischemia resulting from disruption of blood flow during organ harvest and transportation. Histologically, this manifests as variable necrosis in a pattern similar to that seen in systemic hypoperfusion. Calcification of hepatocytes has been rarely observed in ischemic injury due to systemic shock and in two cases of severe IR, both of which were associated with graft loss and death. The authors present another case of dystrophic calcification within hepatocytes occurring in a liver allograft affected by severe IR. Biochemical stains revealed that the mineralized material was calcium phosphate (likely hydroxyapatite). By electron microscopy, the hepatocyte cytoplasm was filled with variably calcified vacuoles, a subset of which likely represented swollen mitochondria. When encountered in hepatic allograft biopsies, hepatocellular calcification is associated with ischemic injury and a poor prognosis.     

Suppression of MAPK and NF-κB Pathways by Limonene Contributes to Attenuation of Lipopolysaccharide-Induced Inflammatory Responses in Acute Lung Injury

The present study aimed to investigate the protective role of limonene in lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS (0.5 mg/kg), and limonene (25, 50, and 75 mg/kg) was injected intraperitoneally 1 h prior to LPS administration. After 12 h, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. Limonene pretreatment at doses of 25, 50, and 75 mg/kg decreased LPS-induced evident lung histopathological changes, lung wet-to-dry weight ratio, and lung myeloperoxidase activity. In addition, pretreatment with limonene inhibited inflammatory cells and proinflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 in BALF. Furthermore, we demonstrated that limonene blocked the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase in LPS-induced ALI. The results presented here suggest that the protective mechanism of limonene may be attributed partly to decreased production of proinflammatory cytokines through the inhibition of NF-κB and MAPK activation.     

Central Administration of Amyloid β-Peptide (25–35) and Individual Features of Cognitive Behavior in Rats

The individual characteristics of cognitive behavior induced by intracerebroventricular administration of aggregated amyloid β-peptide (25–35) (Aβ_25–35) were studied. A new approach to evaluating individual features of the actions of Aβ_25–35 was used. Navigational training was performed in a single brief session using random target positions, and training sessions were repeated a few days later. These experiments produced the first indication that cognitive behavior was undamaged in 50% of the rats at the early stage of Aβ_25–35 exposure. The activities of the antioxidant enzymes superoxide dismutase and catalase in the cortex and hippocampus were significantly decreased in animals with and without cognitive impairments. We suggest that phenotypic characteristics may underlie the individual features of the animals’ responses to Aβ. At the early stage, aggregated Aβ may induce a compensatory reaction which prevents impairment of cognitive processes.     

The Relative Role of Refractoriness and Source–Sink Relationship in Reentry Generation during Simulated Acute Ischemia

During acute myocardial ischemia, reentrant episodes may lead to ventricular fibrillation (VF), giving rise to potentially mortal arrhythmias. VF has been traditionally related to dispersion of refractoriness and more recently to the source–sink relationship. Our goal is to theoretically investigate the relative role of dispersion of refractoriness and source–sink mismatch in vulnerability to reentry in the specific situation of regional myocardial acute ischemia. The electrical activity of a regionally ischemic tissue was simulated using a modified version of the Luo-Rudy dynamic model. Ischemic conditions were varied to simulate the time-course of acute ischemia. Our results showed that dispersion of refractoriness increased with the severity of ischemia. However, no correlation between dispersion of refractoriness and the width of the vulnerable window was found. Additionally, in approximately 50% of the reentries, unidirectional block (UDB) took place in cells completely recovered from refractoriness. We examined patterns of activation after premature stimulation and they were intimately related to the source–sink relationship, quantified by the safety factor (SF). Moreover, the isoline where the SF dropped below unity matched the area where propagation failed. It was concluded that the mismatch of the source–sink relationship, rather than solely refractoriness, was the ultimate cause of the UDB leading to reentry. The SF represents a very powerful tool to study the mechanisms responsible for reentry.     

Betulin Alleviates Myocardial Ischemia–Reperfusion Injury in Rats via Regulating the Siti1/NLRP3/NF-κB Signaling Pathway

Inflammation - To study the effects of betulin (BE) on myocardial ischemia–reperfusion (I/R) injury in rats, electrocardiogram (ECG) was detected by an electrocardiograph; myocardial...     

Suppression of Lung Inflammation in Rats by Prevention of NF-κB Activation in the Liver

Activation of NF-B and production of NF-B-dependent chemokines are thought to be involved in the pathogenesis of neutrophilic lung inflammation. Calpain-1 inhibitor (Cl-1) blocks activation of NF-B by preventing proteolysis of the inhibitory protein IB- by the ubiquitin/proteasome pathway. We hypothesized that inhibition of proteasome function with CI-1 would block NF-B activation in vivo after intraperitoneal (IP) treatment with bacterial lipopolysaccharide (LPS), and that NF-B inhibition would be associated with suppression of chemokine gene expression and attenuation of neutrophilic alveolitis. We treated rats with a single IP injection of CI-1 (10 mg/kg) two hours prior to IP LPS (7 mg/kg). Treatment with CI-1 prevented degradation of IB- and activation of NF-B in the liver in response to LPS; however, CI-1 treatment had no detected effect on NF-B activation in lung tissue. CI-1 treatment prior to LPS resulted in 40% lower MIP-2 concentration in lung lavage fluid compared to rats treated with vehicle prior to LPS (502 +/– 112 pg/ml vs. 859 +/– 144 pg/ml, P < 0.05). In addition, CI-1 treatment substantially inhibited LPS-induced neutrophilic alveolitis (2.7 +/– 1.2 × 10⁵ vs. 43.7 +/– 12.2 × 10⁵ lung lavage neutrophils, P < 0.01). These data indicate that NF-B inhibition in the liver can alter lung inflammation induced by systemic LPS treatment and suggest that a liver-lung interaction contributes to the inflammatory response of the lung.     

Lung Area–Volume Models in Relation to the Recruitment–Derecruitment of Individual Lung Units

The objective of this study was to reconsider some of the previous experimental results in terms of simple geometric models in order to determine if any of the apparent conflicts could be explained within a more unified concept. These models allow individual lung units and the entire lung to expand differently with regard to their area–volume relationship. The effect of a recruitment–derecruitment process as the lung inflates–deflates is also considered. Examples are used to illustrate how some of the apparent conflicts found in the literature may arise from whether or not recruitment and derecruitment take place during lung expansion and contraction. © 2001 Biomedical Engineering Society. PAC01: 8719Uv, 8710+e     

Remifentanil Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Downregulating the NF-κB Signaling Pathway

Remifentanil significantly represses cell immune responses and influences neutrophil migration through endothelial cell monolayers. The present study determines the beneficial effects of remifentanil and the mechanisms by which it attenuates lipopolysaccharide (LPS)-induced acute lung injury (ALI). Rats were intratracheally instilled with 2 mg/kg LPS to induce ALI. Results showed that remifentanil could resolve lung injury, as evidenced by remarkable decreases in lung edema (wet-to-dry weight ratio), neutrophil infiltration (myeloperoxidase activity), and pulmonary permeability [total number of cells and protein concentrations in bronchoalveolar lavage fluid (BALF)]. Remifentanil also attenuated the concentrations of proinflammatory cytokines tumor necrosis factor alpha, interleukin-1β, and interleukin-6 in BALF, as well as effectively repressed the activation of nuclear factor-kappaB (NF-κB), which has been associated with the inhibition of IκBα degradation.These results suggest that remifentanil may be a suitable treatment for LPS-induced ALI. Remifentanil exerts beneficial effects on the inhibition of proinflammatory cytokine production by downregulating the NF-κB pathway.     

Protective Effect of Amygdalin on LPS-Induced Acute Lung Injury by Inhibiting NF-κB and NLRP3 Signaling Pathways

The acute lung injury (ALI) is a leading cause of morbidity and mortality in critically ill patients. Amygdalin is derived from the bitter apricot kernel, an efficacious Chinese herbal medicine. Although amygdalin is used by many cancer patients as an antitumor agent, there is no report about the effect of amygdalin on acute lung injury. Here we explored the protective effect of amygdalin on ALI using lipopolysaccharide (LPS)-induced murine model by detecting the lung wet/dry ratio, the myeloperoxidase (MPO) in lung tissues, inflammatory cells in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines production, as well as NLRP3 and NF-κB signaling pathways. The results showed that amygdalin significantly reduced LPS-induced infiltration of inflammatory cells and the production of TNF-α, IL-1β, and IL-6 in the BALF. The activity of MPO and lung wet/dry ratio were also attenuated by amygdalin. Furthermore, the western blotting analysis showed that amygdalin remarkably inhibited LPS-induced NF-κB and NLRP3 activation. These findings indicate that amygdalin has a protective effect on LPS-induced ALI in mice. The mechanism may be related to the inhibition of NF-κB and NLRP3 signaling pathways.     

Dexamethasone Attenuates LPS-induced Acute Lung Injury through Inhibition of NF-κB,COX-2, and Pro-inflammatory Mediators

Dexamethasone (DEX) is a synthetic glucocorticoid with potent anti-inflammatory effects that is widely used to treat inflammatory diseases. The aim of the present study was to investigate the possible protective effect of DEX on the lipopolysaccharides (LPS)-induced acute lung injury (ALI) in a mouse model. Animals were pretreated with DEX (5 and 10 mg/kg, i.p.) for seven days and acute lung injury was induced by intranasal (i.n.) administration of LPS on day 7. In the present study, administration of LPS resulted in significant increase in neutrophils and lymphocytes count whereas a substantial reduction in T cell subsets (CD3⁺ and CD4⁺) and pro-inflammatory (IL-6 and TNF-α) cytokines occurred, which were reversed by DEX treatment. RT-PCR analysis revealed an increased mRNA expression of IL-6, TNF-α, COX-2, iNOS, and NF-κB p65 and decreased IL-10 in the LPS group, which were reversed by treatment with DEX in lung tissues. Western blot analysis revealed an increased expression of COX-2, iNOS and NF-κB p65 in the LPS-group, which was reduced by treatment with DEX. Compared with the LPS group, the DEX treatment also demonstrated a considerable increase in the protein expression level of IL-10 cytokine. Administration of LPS resulted in marked increase in malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity whereas noticeable decrease in glutathione (GSH) content. These changes were significantly reversed by treatment with DEX. The histological examinations revealed protective effect of DEX while LPS group aggravated lung injury. The present findings demonstrate the potent anti-inflammatory action of the DEX against acute lung injury induced by LPS.