• The Korean Journal of Physiology and Pharmacology
• /
• v.1 no.1
• /
• pp.71-78
• /
• 1997

In an attempt to investigate the role of phospholipase $A_2$($PLA_2$) in interleukin-l (IL-l) induced acute lung injury, mepacrine was tried to inhibit $PLA_2$ in IL-l induced ARDS rats. For confirmation of acute lung injury by IL-l, and to know the role of neutrophils in this injury, lung leak index, lung myeloperoxidase(MPO), number of neutrophils and protein content in the bronchoalveolar lavage (BAL) and wet lung weight were measured. At the same time lung $PLA_2$ was measured to know the effect of IL-l on $PLA_2$ activity. Pulmonary surfactant was also measured for an investigation of type II alveolar cell function. Neutrophil adhesion assay was performed to know the effect of $PLA_2$ inhibition in vitro with human umbilical vein endothelial cells (HUVEC). For precise location of injury by IL-l, morpholgical study was performed by electron microscopy. Five hours after instillation of IL-l (50 ng/rat), lung leak index, protein content, number of neutrophils, lung MPO and wet lung weight were increased significantly. Five hours after IL-l instillation lung $PLA_2$ activity was increased significantly, and increased surfactant release was observed in IL-l induced ARDS rats' BAL. In contrast, in rats given mepacrine and IL-l, there was decrease of acute lung injury i.e. decrease of lung leak index, wet lung weight, protein content, number of neutrophils in BAL and decreased lung MPO activity. Mepacrine decreased surfactant release also. Interestingly, inhibition of $PLA_2$ decreased adhesion of human neutrophils to HUVEC in vitro. Morphologically, IL-l caused diffuse necrosis of endothelial cells, type I and II epithelial cells and increased the infiltration of neutrophils in the interstitium of the lung but after mepacrine treatment these pathological findings were lessened. On the basis of these experimental results it is suggested that $PLA_2$ has a major role in the pathogenesis of acute lung injury mediated by neutrophil dependent manner in IL-l induced acute lung injury.

• Biomedical Science Letters
• /
• v.9 no.1
• /
• pp.37-42
• /
• 2003

The present study was conducted to determine whether administration of heat extract of Lepidii Semen has an inhibitory effect on neutrophil-derived oxidative injury following dermal scald burn in rats. Acute lung injury was induced by scald burn (15% of TBSA) in rats. To identify acute edematous lung injury, protein concentrations and numbers of polymorphonuclear leukocytes were measured in bronchoalveolar lavage (BAL) at 5 h after skin burn. In addition, the level of lung KC (neutrophil chemoattractant cytokine) and activity of lung myeloperoxidase (MPO) were measured, and histopathological changes were observed as well. Lung weight and concentration of BAL protein, the index of lung injury, were clearly increased at 5 h postburn compared with those of sham-operated group. Administration of heat extract of Lepidii Semen after scald burn inhibited the production of KC in lung tissue and decreased the activity of lung MPO related to infiltration of neutrophils. In histopathological changes in lung tissue, infiltration of inflammatory cells and pulmonary edema induced by skin burn were decreased by administration of heat extract of Lepidii Semen after scald burn. These results suggest that Lepidii Semen may be an effective medical stuff for acute lung injury induced by skin burn.

• Biomedical Science Letters
• /
• v.3 no.2
• /
• pp.139-150
• /
• 1997

In order to investigate the effect of aging and the $H_2O$$_2$ localization in association with histological, ultrastructural, and cytochemical studies in lung tissue after interleukin-1$\alpha$(IL-1) induced lung injury, an acute lung injury was induced by instillation of IL-1 into the trachea. Both of 4- and 20-months-old male rats, protein contents in IL-1 treated branchoalveolar lavage increased significantly compared to each control rats. Acute lung injury occured by oxidative stress because neutrophils accumulated in vascular lumen and formed the adhesion with endothelial cells. As these cause, tissue proteins were exuded and leukocytes migrated into the alveolar lumen. Neverthless in these lung injury $H_2O$$_2$ localization of IL-1 treated 20 months rats was not different compared to IL-1 treated 4 months rats. After all aging was not a factor to accelate IL-1 induced lung injury. Based on these results, it is suggested that neutrophil infilteration might be an important cause in acute lung injury, and aging is not a factor to change the acute lung injury by oxidative stress.

• The Korean Journal of Physiology and Pharmacology
• /
• v.2 no.4
• /
• pp.479-491
• /
• 1998

In order to know the pathogenesis of adult respiratory distress syndrome (ARDS) in association with the oxidative stress by neutrophils, the role of platelet activating factor (1-0-alkyl-2-acetyl-snglycero-3-phosphocholine, PAF) was investigated during acute lung injury induced by interleukin- $1{\alpha}$ (IL-1) in rats. An insufflation of IL-1 into the rat's trachea increased the acetyltransferase activity in the lung and the increase of PAF content was followed. As evidences of acute lung injury by neutrophilic respiratory burst, lung leak index, myeloperoxidase activity, numbers of neutrophils in the bronchoalveolar lavage fluid, neutrophilic adhesions to endothelial cells and NBT positive neutrophils were increased after IL-1 treatment. In addition, a direct instillation of PAF into the trachea caused acute lung leak and the experimental results showed a similar pattern in comparison with IL-1 induced acute lung injury. For the confirmation of oxidative stress during acute lung leak by IL-1 and PAF, a histochemical electron microscopy was performed. In IL-1 and PAF treated lungs of rats, the deposits of cerrous perhydroxide were found. To elucidate the role of PAF, an intravenous injection of PAF receptor antagonist, WEB 2086 was given immediately after IL-1 or PAF treatment. WEB 2086 decreased the production of hydrogen peroxide and the acute lung leak. In ultrastructural study, WEB 2086 mitigated the pathological changes induced by IL-1 or PAF. The nuclear factor kappa B (NFkB) was activated by PAF and this activation was inhibited by WEB 2086 almost completely. Based on these experimental results, it is suggested that the PAF produced in response to IL-1 through the remodeling pathway has the major role for acute lung injury by neutrophilic respiratory burst. In an additional experiment, we can also come to conclude that the activation of the NFkB by PAF is thought to be the fundamental mechanism to initiate the oxidative stress by neutrophils causing release of proinflammatory cytokines and activation of phospholipase $A_2$.

• Tuberculosis and Respiratory Diseases
• /
• v.54 no.5
• /
• pp.522-531
• /
• 2003

Background : Hemorrhagic shock and trauma are two of the most common causes of acute lung injury. The activation of cyclooxygenase is one of the important causes of acute lung injury. This study investigated the effect of aspirin, a well-known cyclooxygenase inhibitor, on severe hemorrhage-induced acute lung injury in rats. Methods : The hemorrhagic shock was induced by withdrawing blood; 20ml/kg of B.W., through the femoral artery in 5 min. The mean arterial pressure was recorded through the femoral artery on a polygraph. Results : In the present investigation, the lung tissue myeloperoxidase activity, protein contents and leukocyte counts, in bronchoalveolar lavage fluid, increased significantly 2 and 24 h after the hemorrhage induction. Although the decreased mean arterial pressure spontaneously recovered, acute lung injury occurred after severe hemorrhage. These changes were effectively prevented by a single intravenous injection of aspirin (10 mg/kg of B.W.) 30 min before the hemorrhage. Conclusion : These results suggest that severe hemorrhage-induced acute lung injury is mediated, in part, by the activation of cyclooxygenase. Furthermore, pretreatment of aspirin in acute lung injury-prone patients, or prophylactic treatment of aspirin to the patients with precipitating conditions, could be helpful in the prevention of acute lung injury.

• Tuberculosis and Respiratory Diseases
• /
• v.68 no.6
• /
• pp.334-344
• /
• 2010

Background: Based on the known immunoregulatory functions of moxifloxacin on phagocytes, the therapeutic effect of moxifloxacin on oleic acid (OA)-induced acute lung injury (ALI) was investigated. Methods: Moxifloxacin (10 mg/kg) was given to male Sprague-Dawley rats that had been given oleic acid (OA, $30{\mu}L$) intravenously. Five hours after OA injection, parameters demonstrating ALI were assessed to measure the effects of moxifloxacin on acute lung injury. Results: The pathological findings of OA-induced ALI's was diminished by moxifloxacin. Through ultrastructural and $CeCl_3$ EM histochemistry, moxifloxacin was confirmed to be effective in decreasing oxidative stress in the lung as well. Indices of ALI, such as lung weight/body weight ratio, protein content in bronchoalveolar lavage fluid, and lung myeloperoxidase were decreased by moxifloxacin. In diaminobenzidine immunohistochemistry, fluorescent immunohistochemistry, and Western blotting of the lung, moxifloxacin had decreased the enhanced expression of secretory phospholipase $A_2$ ($sPLA_2$) by OA. Conclusion: We concluded that moxifloxacin was effective in lessening acute inflammatory pulmonary edema caused by OA, by inhibiting the neutrophilic respiratory burst, which was initiated by the activation of $sPLA_2$.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.25 no.1
• /
• pp.55-64
• /
• 2011

The object of this study was to observe the effects of Scutellariae Radix (SR) aqueous extracts on lipopolysaccharide (LPS)-induced rat acute lung injury. Five different dosages of SR extracts were orally administered once a day for 28 days before LPS treatments, and then 5 hours after lipopolysaccharide treatment, all rats were sacrificed. 8 groups, each of 16 rats per group were used in the present study. Changes on the body weights, lung weights, pulmonary transcapillary albumin transit, arterial gas parameters (pH, $PaO_2$ and $PaCO_2$) bronchoalveolar lavage fluid (BALF) protein, lactate dehydrogenase (LDH) and proinflammatory cytokines tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), interleukin-1${\beta}$ (IL-1${\beta}$) contents, total cell numbers, neutrophil and alveolar macrophage ratios, lung malondialdehyde (MDA), myeloperoxidase (MPO), proinflammatory cytokine TNF-${\alpha}$ and IL-1${\beta}$ contents were observed with histopathology of the lung, changes on luminal surface of alveolus (LSA), thickness of alveolar septum, number of polymorphonuclear neutrophils (PMNs). The results were compared with a potent antioxidant ${\alpha}$-lipoic acid, 60 mg/kg, in which the effects on LPS-induced acute lung injury were already confirmed. The results obtained in this study suggest that over 125 mg/kg of SR extracts showed favorable effects on the LPS-induced acute lung injury, and 250 mg/kg of SR extracts resembling acute respiratory distress syndrome mediated by their antioxidant and anti-inflammatory effects and .as similar to ${\alpha}$-lipoic acid in the present study. Therefore, it is expected that SR will be showed favorable effects on the acute respiratory distress syndrome.

• Biomedical Science Letters
• /
• v.27 no.1
• /
• pp.19-27
• /
• 2021

This study was undertaken to clarify the effects of omega-3 fatty acid on endotoxin-induced acute lung injury. Rabbits were randomly assigned to one of four groups. Each group received intravenous infusion of saline only, saline and Escherichia coli endotoxin, omegaven infuison (0.5 mL/kg/hr) and endotoxin, lipoven (0.5 mL/kg/hr) and endotoxin respectively. Infusion of saline was started 0.5 hr before the infusion of saline or endotoxin, and omegaven and lipoven were started 2 hours after endotoxin infusion for 4 hours. The lungs of rabbits were ventilated with 40% oxygen. Mean blood pressure, heart rate, arterial oxygen tension (PaO2), and peripheral blood leukocyte were recorded. The wet/dry (W/D) weight ratio of lung and lung injury score were measured, and analysis of bronchoalveolar lavage fluid (BALF) was done. Endotoxin decreased PaO2, and peripheral blood leukocyte and platelet count. And it increased W/D ratio of lung, lung injury score and leukocyte count, percentage of PMN cells, concentration of IL-8 in BALF. Omegaven attenuated all these changes except for peripheral blood leukocyte counts. Omegaven attenuated endotoxin-induced acute lung injury in rabbits mainly by inhibiting neutrophil and IL-8 responses, which may play a central role in endotoxin-related lung injury.

• The Korean Journal of Physiology and Pharmacology
• /
• v.4 no.3
• /
• pp.219-226
• /
• 2000

In order to elucidate the role of platelet activating factor (PAF) in the acute lung injury induced by endotoxin (ETX), activities of phospholipase A2, lyso PAF acetyltransferase and oxidative stress by neutrophilic respiratory burst were probed in the present study. To induce acute lung injury, $100\;{\mu}g$ of E.coli ETX (type 0127; B8) was instilled directly into the tracheae of Sprague-Dawley rats. Five hours after the ETX instillation, induction of acute lung injury was confirmed by lung leak index and protein contents in the bronchoalveolar lavage (BAL) fluid. At the same time, lung phospholipase A2 (PLA2) activity and expression of group I and II secretory type PLA2 were examined. In these acutely injured rats, ketotifen fumarate, known as lyso PAF acetyltransferase inhibitor and mepacrine were administered to examine the role of PAF in the pathogenesis of the acute lung injury. To know the effect of the ETX in the synthesis of the PAF in the lungs, lyso PAF acetyltransferase activity and PAF content in the lungs were measured after treatments of ETX, ketotifen fumarate and mepacrine. In addition, the role of neutrophils causing the oxidative stress after ETX was examined by measuring lung myeloperoxidase (MPO) and enumerating neutrophils in the BAL fluid. To confirm the oxidative stress in the lungs, pulmonary contents of malondialdehyde (MDA) were measured. After instillation of the ETX in the lungs, lung leak index increased dramatically (p＜0.001), whereas mepacrine and ketotifen decreased the lung leak index significantly (p＜0.001). Lung PLA2 activity also increased (p＜0.001) after ETX treatment compared with control, which was reversed by mepacrine and ketotifen (p＜0.001). In the examination of expression of group I and II secretory PLA2, mRNA synthesis of the group II PLA2 was enhanced by ETX treatment, whereas ketotifen and WEB 2086, the PAF receptor antagonist, decreased the expression. The activity of the lysoPAF acetyltransferase increased (p＜0.001) after treatment of ETX, which implies the increased synthesis of PAF by the remodelling of lysoPAF in the lungs. Consequently, the contents of the PAF in the lungs were increased by ETX compared with control (p＜0.001), while mepacrine (p＜0.001) and ketotifen (p＜0.01) decreased the synthesis of the PAF in the lungs of ETX treated rats. The infiltration of the neutrophils was confirmed by measuring and enumerating lung MPO and the neutrophils in the BAL fluid respectively. Compared with control, ETX increased lung MPO and number of neutrophils in BAL significantly (p＜0.001) whereas mepacrine and ketotifen decrerased number of neutrophils (p＜0.001) and MPO (p＜0.05, p＜0.001, respectively). The lung MDA contents were also increased (p＜0.001) by ETX treatment, but treatment with mepacrine (p＜0.001) and ketotifen (p＜0.01) decreased the lung MDA contents. Collectively, we conclude that ETX increases PLA2 activity, and that the subsequently increased production of PAF was ensued by the remodelling of the lyso PAF resulting in tissue injury by means of oxidative stress in the lungs.

• 대한상한금궤의학회지
• /
• v.13 no.1
• /
• pp.21-44
• /
• 2021

Objective : This study aimed to assess the preventive effect of Bupleuri Radix aqueous extracts (BR) and red koji-fermented BR (fBR) in lipopolysaccharide (LPS)-induced acute lung injury in a rat model. Methods : Rats were administered 30, 60, or 120 mg/kg/day of fBR for 28 days before LPS treatments. All rats were sacrificed 5 h after LPS treatment (500 ㎍/head, intratracheal instillation). Body weights, lung weights, pulmonary transcapillary albumin transit, arterial gas parameters (pH, partial pressure [Pa] of O2, PaCO2), bronchoalveolar lavage fluid (BALF) protein, lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), total cell numbers, neutrophil/alveolar macrophage ratios, lung malondialdehyde (MDA), and myeloperoxidase (MPO) were measured. In addition, histopathological changes including the luminal surface of alveoli (LSA), thickness of alveolar septum, and number of polymorphonuclear neutrophils (PMNs) were checked. Results : LPS injection led to increases in lung weights, pulmonary transcapillary albumin transit, BALF protein, LDH, TNF-α and IL-1β contents, total cells, neutrophil and alveolar macrophage ratios, lung MDA, MPO, alveolar septum thickness, and PMNs, and decreases in PaCO2 and pH of arterial blood and LSA. However, these LPS-induced acute lung injuries were inhibited by pretreatment of 30, 60, and 120 mg/kg of fBR. The most favorable effects were seen with 30 mg/kg fBR as compared with 60 mg/kg of α-lipoic acid and BR. Conclusions : fBR showed preventive effects on LPS-induced acute lung injury, which resembles acute respiratory distress syndrome. The mechanisms of action were likely via antioxidant and anti-inflammatory means.