• Tuberculosis and Respiratory Diseases
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• v.48 no.4
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• pp.487-499
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• 2000

Background : Acute lung injury is an hypoxic respiratory failure resulting from damage to the alveolar-capillary membrane, which can be developed by a variety of systemic inflammatory diseases. In this study the therapeutic effects of intra-tracheal pulmonary surfactant instillation was evaluated in the intratracheal endotoxin induced acute lung injury model of a rat. Methods : Twenty Sprague-Dawley rats were divided into 4 groups, and normal saline (2 ml/kg, for group 1) or LPS (5 mg/kg, for group 2, 3, and 4) was instilled into the trachea respectively. Either normal saline (2 ml/kg, for group 1 & 2, 30 min later) or bovine surfactant (15 mg/kg, 30 min later for group 3, 5 hr later for group 5) was instilled into the trachea. The therapeutic effect of intratracheal surfactant therapy was evaluated with one chamber body plethysmography (respiratory frequency, tidal volume and enhanced pause), ABGA, BAL fluid analysis (cell count with differential, protein concentration) and pathologic examination of the lung. Results : Intratracheal endotoxin instillation increased the respiration rate decreased the tidal volume and int creased the Penh in all group of rats. Intratracheal instillation of surfactant decreased Penh, increased arterial oxygen tension, decreased protein concentration of BAL fluid and decreased lung inflammation at both times of administration (30 minute and 5 hour after endotoxin instillation). Conclusion : Intratracheal instillation of surfactant can be a beneficial therapeutic modality as discovered in the acute lung injury model of rats induced by intratracheal LPS intillation. It deserves to be evaluated for treatment of human acute lung injury.

• Tuberculosis and Respiratory Diseases
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• v.63 no.3
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• pp.294-298
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• 2007

Pulmonary alveolar proteinosis is a rare disorder that is characterized by the abundant accumulation of surfactant-derived material within the alveolar spaces and distal bronchioles. Although the findings of homogenous ground-glass opacities overlaid by thickened septa, which form a "crazy paving" pattern on high-resolution computed tomography, can assist in making a diagnosis, a lung biopsy is usually required. This disorder has a variable clinical course, from spontaneous resolution to respiratory failure and death. While a whole lung lavage has been the standard treatment since the early 1960s, GM-CSF therapy has been attempted based on the recently suggested pathogenetic mechanism. We report a case of pulmonary alveolar proteinosis that resolved spontaneously after an open lung biopsy.

• Tuberculosis and Respiratory Diseases
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• v.52 no.4
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• pp.411-418
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• 2002

Pulmonary alveolar proteinosis(PAP) is a disorder in which an insoluble, proteinaceous material, rich in phospholipids, is deposited in the alveoli and bronchioles. The deficiency in the clearance and degradation of the intra-alveolar phospholipoproteinaceous material in PAP most likely represents a dysfunction of the type II pneumocytes. Although the pathogenesis and causative treatment of PAP is unclear a whole lung bronchopulmonary lavage is a relatively safe and effective treatment. Here we experienced a case of pulmonary alveolar proteinosis in a 62 year old female patient who had pulmonary tuberculosis approximately 20 years ago. She complained of aggravated dyspnea and chronic cough, and presented fine inspiratory crackles at both lung fields, diffuse ground glass opacity with some area of consolidation and smooth interlobular septal thickenings in both upper, right middled lobes, and a portion of right lower lobe. Optical microscopy of the lung tissue obtained by and open lung biopsy revealed many granulomas containing acid-fast smear positive bacilli and diffuse homogeneous PAS-positive fluid in the alveolar space. Immunohistochemical stain showed surfactant. A in the alveolar space. Antituberculosis drugs with bronchoalveolar lavage were used to treat the disease. Thereafter she showed improvement in her symptoms and a partial improvement in the chest X-ray and HRCT findings. We present a case of PAP associated with pulmonary tuberculosis.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.5
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• pp.617-628
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• 1998

In order to understand the pathogenetic mechanism of adult respiratory distress syndrome (ARDS), the role of phospholipase A2 (PLA2) in association with oxidative stress was investigated in rats. $Interleukin-1{\alpha}\;(IL-1,\;50\;{\mu}g/rat)$ was used to induce acute lung injury by neutrophilic respiratory burst. Five hours after IL-1 insufflation into trachea, microvascular integrity was disrupted, and protein leakage into the alveolar lumen was followed. An infiltration of neutrophils was clearly observed after IL-1 treatment. It was the origin of the generation of oxygen radicals causing oxidative stress in the lung. IL-1 increased tumor necrosis factor (TNF) and cytokine-induced neutrophil chemoattractant (CINC) in the bronchoalveolar lavage fluid, but mepacrine, a PLA2 inhibitor, did not change the levels of these cytokines. Although IL-1 increased PLA2 activity time-dependently, mepacrine inhibited the activity almost completely. Activation of PLA2 elevated leukotriene C4 and B4 (LTC4 and LTB4), and 6-keto-prostaglandin $F2{\alpha}\;(6-keto-PGF2{\alpha})$ was consumed completely by respiratory burst induced by IL-1. Mepacrine did not alter these changes in the contents of lipid mediators. To estimate the functional changes of alveolar barrier during the oxidative stress, quantitative changes of pulmonary surfactant, activity of gamma glutamyltransferase (GGT), and ultrastructural changes were examined. IL-1 increased the level of phospholipid in the bronchoalveolar lavage (BAL) fluid, which seemed to be caused by abnormal, pathological release of lamellar bodies into the alveolar lumen. Mepacrine recovered the amount of surfactant up to control level. IL-1 decreased GGT activity, while mepacrine restored it. In ultrastructural study, when treated with IL-1, marked necroses of endothelial cells and type II pneumocytes were observed, while mepacrine inhibited these pathological changes. In histochemical electron microscopy, increased generation of oxidants was identified around neutrophils and in the cytoplasm of type II pneumocytes. Mepacrine reduced the generation of oxidants in the tissue produced by neutrophilic respiratory burst. In immunoelectron microscopic study, PLA2 was identified in the cytoplasm of the type II pneumocytes after IL-1 treatment, but mepacrine diminished PLA2 particles in the cytoplasm of the type II pneumocyte. Based on these experimental results, it is suggested that PLA2 plays a pivotal role in inducing acute lung injury mediated by IL-1 through the oxidative stress by neutrophils. By causing endothelial damage, functional changes of pulmonary surfactant and alveolar type I pneumocyte, oxidative stress disrupts microvascular integrity and alveolar barrier.

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

• The Korean Journal of Physiology
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• v.5 no.1
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• pp.51-58
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• 1971

In an attempt to further clarify the effect of X·irradiation on the activity of surfactant in rabbits, X-ray in dose of 900r was irradiated to the lung tissues of rabbits in vitro. Tension-area diagram of the lung extract was recorded automatically by a modified Langmuir-Wilhelmy balance with a synchronized recording system designed in this department. The surface tension of the lung extract was measured at 1,3,5,24 and 48 hours post-irradiation, and the results were compared with the non·irradiated normal group. The result$ thus obtained are summarized as follows: I The maximal surface tension, minimal surface tension, width of the tension·area diagram at the surface area of 40% in the lung extract and stability index of the normal rabbit long extract were 40.73 dynes/cm, 8.96 dynes/cm, 20.71 dynes/cm and 1.28, respectively. II. When 900r of X-ray was irradiated to the lung in vitro, 1) The maximal and minimal surface tensions did not differ noticeably from the normal at 1,3, and 5 post-irradiation hours, but the minimal surface tension increased significantly at 24 and 48 hours Post-irradiation. 2) The width of the tension area at the surface area of 40% showed a tendency of decrease throughout the experiment. 3) The stability index showed no significant change at 1,3 and 5 post-irradiation hours,but at 24 and 48 hours post-irradiation a significant decrease was observed comparing with the control. III. Activity of surfactant was significantly depressed by X·irradiation in vitro especially at 24 and 48 hours post-irradiation.

• Tuberculosis and Respiratory Diseases
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• v.48 no.6
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• pp.887-897
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• 2000

Background : Since the exact pathogenesis of sepsis-induced ARDS has not been elucidated, the mechanisms of enhanced neutrophilic respiratory burst were probed in endotoxin primed neutrophils associated with the roles of phospholipase A2(PLA2), platelet activating factor(PAF) and apoptosis. Methods : In isolated fresh human neutrophils, effects of the inhibition of PLA2 and PAF on the apoptosis were examined by the method of Annexin-FITC/dual PIflow cytometry. The roles of PLA2 and PAF on the neutrophilic respiratory burst were also examined by measuring oxidant generation in cytochrome-c reduction assay. Activities of the PLA2 and lysoPAF acetyltransferase (lysoPAF AT) of the neutrophils were determined to understand the effect of endotoxin on these enzymatic activities which may be related to the neutrophilic respiratory burst and apoptosis. In addition, the role roles of PLA2 and PAF in neutrophilic adhesion to bovine endothelial cells were examined in vitro by neutrophil adhesion assay. To investigate the effect of oxidants on pulmonary surfactant, cytochemical ultrastructural microscopy was performed. To inhibit PLA2 and PAF, non-specific PLA2 inhibitor mepacrine (100 nM) and WEB 2086 (100 nM) or ketotifen fumarate (10 ${\mu}g$/ml) were used respectively in all in vitro experimental sets. WEB 2086 is PAF receptor antagonist, and ketotifen fumarate is a lyso PAF AT inhibitor. Results: The mapacrine treatment, provided and the endotoxin (ETX) treatment, resulted in increased apoptosis of neutrophils (p<0.001) while treatments of WEB 2086 and ketotifen did not. The inhibition of PLA2 and PAF decreased (p<0.001) production of oxidants from PMA-stimulated neutrophils. While endotoxin increased the PLA2 activity of neutrophils (p<0.01), mepacrine supressed (p<0.001) the activity, provided after treatment of ETX. The lyso PAF actyltransferase activity (lyso PAF AT) increased (p<0.01) after treatment of ETX. In contrast, mepacrine, WEB 2086 and ketotifen showed a tendency of decreasing the activity after treatment of ETX. The treatment of ETX incresed (p<0.001) neutrophil adhesion to endothelial cells, which was reversed by inhibition of PLA2 and PAF (p<0.01). The binding of oxidants to pu1monary surfactant was identified histologically. Conclusions : The enhanced neutrophilic respiratory burst by ETX plays a pivotal role in the pathogenesis of ARDS in terms of oxidayive oxidative stress. Increased production of oxidants from neutrophils is mediated by the activations of PLA2 and lyso PAF AT.

• The Korean Journal of Physiology
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• v.7 no.2
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• pp.1-8
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• 1973

Though it has been reported by Clements et al. and Avery et al. that the activity of the pulmonary surfactant can be altered by the temperature changes, a conclusive evidence of the effects of temperature on the surfactant system of the lung is yet to come. In the present study, an attempt was made to observe possible effects of a few different degrees of temperature on the activity of the pulmonary surfactant of the rabbit in vivo and in vitro. The rabbit was sacrificed by blood shedding and both lungs were completely removed. The lung washings, obtained by gently lavaging the left lung with saline, was placed at 1) 4C for 1, 5, 10, 15, 30 and 40 days, and 2) 20C for 1, 2, 3, 4, 5 and 7 days for in vitro experiment. For in vivo experiment, the rabbit was placed at 4C for 4, 8, 12 and 24 hours, and the lung lavage was prepared as described above in the in vitro experiment. Tension-area (T-A) diagram of the lung lavage was recorded automatically by a modified. Langmuir-Wilhelmy balance with a synchronized recording system. The surface tensions thus obtained were compared with those of the normal rabbit, and the results are summarized as follows: 1. The maximal surface tension, minimal surface tension and stability index of the normal rabbit lung lavage were $52.5{\pm}2.3\;dynes/cm,\;4.9{\pm}2.3\;dynes/cm$ and 1.65, respectively. 2. In the group where the lung lavage was placed at 4C in vitro, the maximal and minimal surface tensions, and stability index did not show any noticeable changes comparing with the normal values up to 30 days. On the 40th day of the experiment, a tendency of a slight increase in the surface tensions was observed but the change was not significant. 3. When the lung lavage was placed at 20 C in vitro, the maximal surface tension did not show any appreciable change comparing with the normal except on the 7 th day with a slight increase. The minimal surface tension showed an increased value from the 2nd day, and on the 5 th and 7 th experimental day, markedly increased value was observed. The stability index, on the other hand. showed a marked decrease throughout the entire experiment with the value of 0.71 and 0.53 on the 5th and 7 th day, respectively. 4. In the group where the rabbit was placed at 4 C in vivo, the maximal surface tensions and stability index of the lung lavage showed little change from the normal. The minimal surface tension at 12 experimental hour showed a slight increase, but it returned to the normal value at 24 hour.

• Clinical and Experimental Pediatrics
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• v.60 no.7
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• pp.232-236
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• 2017

Pulmonary alveolar proteinosis (PAP) is a rare disease in children characterized by intra-alveolar accumulation of surfactant proteins, which severely reduces gaseous exchange. Whole lung lavage (WLL) is the preferred technique for the treatment of severe PAP. Herein, we present a pediatric case of PAP treated with WLL. An 11-year-old boy was admitted with the chief complaint of a dry cough lasting 6 months. He developed symptoms of dyspnea on exertion and had difficulty in climbing stairs. He was ultimately diagnosed with PAP through video-assisted thoracoscopic lung biopsy. As first-line of treatment for PAP, he underwent therapeutic WLL for each of his lungs on separate days. After a brief recovery, his symptoms gradually worsened; therefore, he underwent a second WLL. This is the first pediatric case of PAP relapse despite successful WLL in Korea.

• The Korean Journal of Physiology
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• v.17 no.1
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• pp.23-28
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• 1983

In order to clarify the effect of steroid on the pulmonary pressure-volume curve in the pneumonectomized rabbit, the right side pneumonectomy was performed under general anesthesia with pentobarbital sodium and the remaining lung was excised on the fifth day after surgery. The intrapulmonic pressure in the excised left lung was measured at 20, 25, and 30 ml lung volume during inflation and deflation period. In the steroid treated group, the intrapulmonic pressure at 20, 25, and 30 ml lung volume during inflation was significantly decreased compared with intrapulmonic pressure of the control group. But in the pneumonectomy group the decreasing tendency of the pressure was observed. During deflation, the intrapulmonic pressure at 25 ml and 20 ml was not significantly different from the control group in pneumonectomy and steroid treated pneumonectomy group. And the lung weight was measured in each experimental group and also the lung weightbody weight ratio(L/B) was calculated. The lung weight was significantly increased in both pneumonectomy and steroid treated pneumonectomy group. Calculated L/B was increased significantly in both group. Above results suggest that steroid increases the secretion of pulmonary surfactant or affects the catabolic effect on protein metabolism of connective tissue in lung parenchyma.