• Tuberculosis and Respiratory Diseases
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• v.42 no.1
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• pp.58-66
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• 1995

Background: Acute interstitial pneumonia is a relatively rare form of interstitial pneumonia, since the vast majority of interstitial pneumonia have a more chronic course. It corresponds to the lesion described by Hamman and Rich, as Hamman-Rich disease in 1944. Another name in the clinical literature is accelerated interstitial pneumonia, idiopathic acute respiratory distress syndrome (idiopathic ARDS), and the organizing stage of diffuse alveolar damage. Acute interstitial pneumonia differs from chronic interstitial pneumonia by clinical and pathologic features. Clinically, this disease is characterized by a sudden onset and a rapid course, and reversible disease. Method and Purpose: Five cases of pathologically proven acute interstitial pneumonia were retrospectively studied to define the clinical, radiologic, and pathologic features. Results: 1) The five cases ranged in age from 31 to 77 years old. The onset of illness was acute in all patients, it began with viral-like prodrome 6~40 days prior to shortness of breath, and respiratory failure eventually developed in all patients. In 2 cases, generalized skin rash was accompanied with flu-like symptoms. Etiologic agent could not be identified in any case. 2) All patients had leukocytosis and severe hypoxemia. Pulmonary function test of 3 available cases shows restrictive ventilatory defect, and one survived patient(case 5) has a complete improvement of pulmonary function after dismissal. 3) Diffuse bilateral chest infiltrates were present radiologically. Theses were the ground-glass, consolidation, and reticular densities without honeycomb fibrosis in all patients. The pathologic abnormalities were the presence of increased numbers of macrophages and the formation of hyaline membranes within alveolar spaces. There was also interstitial thickening with edema, proliferation of immature fibroblast, and hyperplasia of type II pneumocyte. In the survived patient(case5), pathologic findings were relatively early stage of acute interstitial pneumonia, such as hyaline membrane with mild interstitial fibrosis. 4) Of the 5 patients, four patients died of respiratory failure 14~90 days after onset of first symptom, and one survived and recovered in symptoms, chest X ray, and pulmonary function test Conclusion: These results emphasize that acute interstitial pneumonia is clinically, radiologically, and pathologically distinct form of interstitial pneumonia and should be separated from the group of chronic interstitial pneumonia. Further studies will be needed to evaluate the pathogenesis and the treatment of acute interstitial pneumonia.

• Tuberculosis and Respiratory Diseases
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• v.43 no.1
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• pp.63-68
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• 1996

Background: Interferon-$\gamma$ has various biologic effects, including antiviral effect, antitumor proliferative effect, activation of macrophage and B lymphocyte, and increased expression of major histocompatibility complex. Especially, antitumor proliferative effect of interferon-$\gamma$ has already been proved to be important in vivo as well as in vitro. And, clinical studies of interferon-$\gamma$ have been tried in lung cancer patients. However, the mechanism of antitumor effect of interferon-$\gamma$ has not yet been established despite of many hypotheses. "Necrosis" is a type of cell death which is well known to occur in the circumstances of severe stresses. In contrast, "apoptosis" is another type of cell death which occurs in such biological circumstances as embryonic development, regression of organs, and self-tolerance of lymphocytes. And, apoptosis is an active process of cell death in which cells are dying with fragmentations of their cytoplasms and nuclei. And, in the process of apoptosis the DNAs of cells are cleaved between nucleosomes by unidentified endonuclease and therefore DNAs of apoptotic cells result in a typical electrophoresis pattern known as DNA ladder pattern. Recently it has been suggested that cytotoxic effect of interferon-$\gamma$ occurs via apoptosis. To elucidate the mechanism of antitumor cytotoxic effect of interferon-$\gamma$, we microscopically observed a lung cancer cell line, A549 which was treated with interferon-$\gamma$. We observed A545 treated with interferon-$\gamma$ was dying fragmented. And so, we performed this study to find out that the mechanism of antitumor cytotoxic effect of interferon-$\gamma$ be apoptosis. Method: We treated A549, human lung cancer cell line with various concentration of interferon-$\gamma$ and quantified its cytotoxic effect of various periods, 24 hours, 72 hours and, 120 hours by MTT(dimethylthiazolyl diphenyltetrazolium bromide) bioassay. Also, after we treated A549 with 100 units/mi of interferon-$\gamma$ for 120 hours, we observed the pattern of cell death with inverted microscope and we extracted DNAs from the dead A549 cells and observed the pattern of 1.5% agarose gel electrophoresis with ethidium bromide staining. Result: 1) Cytotoxic effect of interferon-$\gamma$ on A549: For the first 24 hours, threre was little cytotoxic effect and for between 24 hours and 72 hours, there was the beginning of cytotoxic effect and for 120 hours there was increased cytotoxic effect. 2) Pattern of A549 cell death by interferon-$\gamma$: We observed with inverted microscope that A549 cells were dying fragmented. 3) DNA ladder pattern of gel electrophoresis: We observed DNA ladder pattern of gel electrophoresis of extracted DNAs from dead A549 cells. Conclusion: We concluded that the mechanism of interferon-$\gamma$induced cytotoxicity on lung cancer cell line, A549 be via apoptosis.

• Tuberculosis and Respiratory Diseases
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• v.65 no.3
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• pp.177-182
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• 2008

Background: Isoniazid (INH, H) is a key drug of the standard first-line regimen for the treatment of tuberculosis (TB), yet some reports have suggested that treatment efficacy was maintained even though INH was omitted from the treatment regimen. Methods: One hundred forty C57BL/6 mice were infected with the H37Rv strain of M. tuberculosis with using a Glas-Col aerosol generation device, and this resulted in depositing about 100 bacilli in the lung. Four weeks after infection, anti-TB treatment was initiated with varying regimens for 4-8 weeks; Group 1: no treatment (control), Group 2 (4HREZ): 4 weeks of INH, rifampicin (R), pyrazinamide (Z) and ethambutol (E), Group 3: 1HREZ/3REZ, Group 4: 4REZ, Group 5: 4HREZ/4HRE, Group 6: 1HREZ/3REZ/4RE, and Group 7: 4REZ/4RE. The lungs and spleens were harvested at several time points until 28 weeks after infection, and the colony-forming unit (CFU) counts were determined. Results: The CFU counts increased steadily after infection in the control group. In the 4-week treatment groups (Group 2-4), even though the culture was negative at treatment completion, the bacilli grew again at the 12-week and 20-week time points after completion of treatment. In the 8-week treatment groups (Groups 5-7), the bacilli did not grow in the lung at 4 weeks after treatment initiation and thereafter. In the spleens of Group 7 in which INH was omitted from the treatment regimen, the culture was negative at 4-weeks after treatment initiation and thereafter. However, in Groups 5 and 6 in which INH was taken continuously or intermittently, the bacilli grew in the spleen at some time points after completion of treatment. Conclusion: TThe exclusion of INH from the standard first-line regimen did not affect the treatment outcome in a murine model of TB in the early stage of disease. Further studies using a murine model of chronic TB are necessary to clarify the role of INH in the standard first-line regimen for treating TB.

• Tuberculosis and Respiratory Diseases
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• v.40 no.1
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• pp.6-15
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• 1993

Background: Positive end, expiratory pressure (PEEP) has become one of the standard therapies for adult respiratory distress syndrome (ARDS). Total static compliance has been proposed as a guide to determine the size of PEEP ('best PEEP') which is of unproven clinical benefit and remains controversial. Besides increasing functional residual capacity and thus improving oxygenation, PEEP stimulate prostacyclin secretion and was proposed for the treatment of acute pulmonary embolism. But little is known about the effect of PEEP on hemodynamic and gas exchange disturbances in acute pulmonary embolism. Methods: To study the validity of total static compliance as a predictor of 'best PEEP' in ARDS and acute pulmonary embolism, experimental ARDS was induced in mongrel dog with oleic acid and acute pulmonary embolism with autologous blood clot. Then hemodynamic and gas exchange parameters were measured with serial increment of PEEP. Results:In ARDS group, total static compliance and oxygen transport were maximal at 5 cm$H_2O$, and decreased thereafter (p<0.05). With increment of PEEP, arterial oxygen tension ($PaO_2$) and arterial carbon dioxide tension ($PaCO_2$) increased and cardiac output and physiological shunt decreased. In pulmonary embolism group, total static compliance, oxygen transport, physiological shunt and cardiac output decreased and $PaO_2$ and $PaCO_2$ increased with increment of PEEP (p<0.05). Comparing the change induced by increment of PEEP by 1 cm$H_2O$ in ARDS group with that in pulmonary embolism group, there was no significant difference between two groups except cardiac output which decreased more in pulmonary embolism group (p<0.05). In ARDS group, oxygen transport and total static compliance increased after PEEP application, and total static compliance was maximal at the PEEP level where oxygen transport was maximal. However in pulmonary embolism group, oxygen transport and total static compliance decreased after application of PEEP. There was significant correlation between change of total static compliance and change of oxygen transport in both groups. Conclusion: In both ARDS and acute pulmonary embolism, it can be concluded that total static compliance is useful as a predictor of 'best PEEP'.

• Tuberculosis and Respiratory Diseases
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• v.41 no.5
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• pp.504-512
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• 1994

Background: It is well known that severe hypoxemia is often associated with liver cirrhosis without preexisting cardiac or pulmonary diseases. Pulmonary vascular impairments, more specifically, intrapulmonary shunting have been considered as a major mechanism. Intrapulmonary shunting arises from pulmonary vascular dilatation at the precapillary level or direct arteriovenous communication and has relationship with the characteristic skin findings of spider angioma. However, these results are mainly from Western countries where alcoholic and primary biliary cirrhosis are dominant cuases of cirrhosis. It is uncertain that the same is true in viral hepatitiss associated liver cirrhosis, which is dominant causes of liver cirrhosis in Korea. We investigated the incidences of hypoxemia and orthodeoxia in Korean cirrhotic patients dominantly composed of postnecrotic cirrhosis and the significance of intrapulmonary shunting as the suggested mechanism of hypoxemia, Method: We performed the arterial blood gas analysis separately both at the supine and errect position in 48 stable cirrhotic patients without the evidences of severe complications such as ascites, variceal bleeding, and hepatic coma. According to the results of arterial blood gas analysis, all patients were divided into hypoxemic and normoxemic group. In each group, pulmonary function test and Tc-99m-MAA whole body scan were performed. The shunting fraction was calculated based on the fact that the sum of cerebral and bilateral renal blood flow is 32% of the systemic blood flow. Results: The hypoxemia of $PaO_2$ less than 80 mmHg was observed in 9 patients(18.8%) and Orthodeoxia more than 10 mmHg was observed in 8 patients(16.7%). But there was no patient with significant hypoxemia of $PaO_2$ less than 60 mmHg. $PaO_2$ was significantly decreased in the patients with spider angioma than the pathients without spider angioma and showed no correlation with the serologic type and severities of liver function test findings. Any parameters of pulmonary function test did not demonstrate the difference between normoxemic and hypoxemic group. But hypoxemic group showed significantly increased shunt fraction of $11.4{\pm}4.1%$ than normoxemic group of $4.1{\pm}2.0%$ (p<0.05). Conclusions: Hypoxemia is not infrequently observed complication in liver cirrhosis and intrapulmonary shunting is suggested to p1ay a major ro1e in the development of hypxemia. But there was no great likelihood of clinically significant hypoxemia in our domestic cirrhotic patients predominantly composed of postnecrotic type.

• Tuberculosis and Respiratory Diseases
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• v.48 no.5
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• pp.766-772
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• 2000

Background : Pressure rise time (PRT) is the time in which the ventilator aclieves the set airway pressure in pressure-targeted modes, such as pressure control ventilation (PCV). With varying PRT, in principle, the peak inspiratory flow rate of the ventilator also varies. And if PRT is set to a shorter duration, the effective duration of target pressure level would be prolonged, which in turn would increase inspiratory tidal volume(Vti) and mean airway pressure (Pmean). We also postulated that the increase in Vti with shortening of PRT may relate inversely to the patients' basal airway resistance. Methods : In 13 paralyzed patients on PCV (pressure control 18$\pm$9.5 cm $H_2O$ $FIO_2\;0.6\pm0.3$, PEEP 5$\pm$3 cm $H_2O$, f 20/min, I : E1 : 2) with Servo 300 (Siemens-Elema, Solna, Sweden) from various causes of respiratory failure, PRT of 10 %, 5 % and 0 % were randomly applied. At 30 min of each PRT trial, peak inspiratory flow (PIF, L/sec), Vti (ml), Pmean (cm $H_2O$) and ABGA were determined. Results : At PRT 10%, 5%, and 0%, PIF were 0.69$\pm$0.13, 0.77$\pm$0.19, 0.83$\pm$0.22, respectively (p<0.001). Vti were 425$\pm$94, 439$\pm$101, 456$\pm$106, respectively (p<0.001), and Pmean were 11.2$\pm$3.7, 12.0$\pm$3.7, 12.5$\pm$3.8, respectively (p<0.001). pH were 7.40$\pm$0.08, 7.40$\pm$0.92, 7.41$\pm$0.96, respectively (p=0.00) ; $PaCO_2$ (mm Hg) were 47.4$\pm$15.8, 47.2 $\pm$15.7, 44.6$\pm$16.2, respectively (p=0.004) ; $PAO_2-PaO_2$ (mm Hg) were 220$\pm$98, 224$\pm$95, 227$\pm$94, respectively (p=0.004) ; and $V_n/V_T$ as determined by ($PaCO_2-P_E-CO_2$)/$PaCO_2$ were 0.67$\pm$0.07, 0.67$\pm$0.08, 0.66$\pm$0.08, respectively (p=0.007). The correlation between airway resistance and change of Vti from PRT 10% to 0% were r= -0.243 (p=0.498). Conclusion : Shortening of pressure rise timee during PCV was associated with increased tidal volume, increased mean airway pressure and lower $PaCO_2$.

• Tuberculosis and Respiratory Diseases
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• v.46 no.5
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• pp.697-708
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• 1999

Background : Leukotriene (LT) $C_4$, $D_4$, and $E_4$, the main components of slow-reacting substance of anaphylaxis (SRS-A), have been suggested to play an important role in bronchial asthma such as antigen-induced bronchoconstriction, airway hyperreactivity, and pulmonary eosinophil accumulation. The purpose of this study was to evaluate the effects of treatment with the cysteinyl-LTs (cys-LTs) antagonist, pranlukast on allergen-induced guinea pig asthma model. Methods : Guinea pigs of treatment and placebo groups were sensitized by subcutaneous injection of ovalbumin(OVA) and challenged by inhalation of aerosolized OVA (1% weight/volume OVA). Normal control group did not sensitize with OVA. Oral ingestion of pranlukast and normal saline to the treatment and placebo groups was performed. In the treatment and placebo groups, airway resistance was measured before and after oral ingestion. Serum $LTC_4$ and eosinophilic infiltration of the bronchiolar and peribronchiolar tissues were measured after ingestion in the treatment and placebo groups. Results : Allergen-induced airway constriction developed in 20 (8 in treatment group, 12 in placebo group) among 35 guinea pigs. Airway resistance was significantly decreased at 3 and 6 minutes after OVA challenge in the pranlukast treatment group. In the placebo group, there was no difference of airway resistance between before and after saline ingestion. Serum $LTC_4$ levels showed 348.4 pg/ml in the treatment group, 373.9 pg/ml in the placebo group, and 364.4 pg/ml in the control group. There were no statistically significant difference between treatment and placebo group (p=0.232), and treatment and control group (p=0.501). Eosinophilic infiltrations in the peribronchiolar region per one-microscopic field ($\times$400 high power fields) demonstrated 7.06 in the treatment group, 19.2 in the placebo group, and 4.50 in the control group. There was significant decrement of eosinophilic infiltration in the treatment group which was compared with placebo group (p=0.001). Conclusion : These results demonstrate that pranlukast, a cys-LTs receptor antagonist, can attenuate allergen induced early-phase bronchoconstriction and eosinophilic infiltration in the bronchiolar tissues.

• Tuberculosis and Respiratory Diseases
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• v.46 no.2
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• pp.241-250
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• 1999

Background: Persistent nonproductive cough is a major adverse effect encountered with ACE inhibitor treatment and the most frequent reason for withdrawal of the drug. The mechanism of cough was postulated to be associated with accumulation of bronchial irritants which are substrates of ACE. It has been speculated that occurrence of this adverse effect is genetically predetermined ; in particular, variants of the genes encoding ACE. To investigate this relationship, we determined ACE gene Insertion/Deletion polymorphism in subjects with and without a history of ACE inhibitor-induced cough. Methods: Among the 339 patients with ACE inhibitor treatment, subjects who developed cough that resolved when not taking medication were designated to cough group and other subjects who did not complain cough were designated to non-cough group. Clinical characteristics of the patients were collected by review of medical records. ACE genotypes were determined by PCR amplification of DNA from peripheral blood and agarose gel electrophoresis. Results: 37 patients complained of dry cough(cough group) and 302 patients did not complained of cough(non-cough group). The incidence of ACE inhibitor induced dry cough was 10.9%. There was a preponderance of females in the cough group (M : F=24.3% : 75.7%) compared to the non-cough group (M : F=49.7% : 50.3%, p=0.004). There was no significant difference in mean age, underlying diseases, and kinds and frequencies of ACE inhibitors and their mean dosage between the both groups. ACE genotypic frequencies were I/I : I/D : D/D=16.2% : 18.9% : 64.9% in the cough group and 18.9% : 18.2% : 62.9% in the non-cough group which showed no significant difference between the both groups(p=0.926). Allelic frequencies were I : D = 25.7% : 74.3% and 28.0% : 72.0% in the cough and non-cough group respectively and the difference was not significant(p = 0.676). Conclusion: The incidence of ACE inhibitor-induced cough are 10.9%, and women are more susceptible to ACE inhibitor-induced cough. ACE inhibitor-induced dry cough is not associated with ACE gene Insertion/Deletion polymorphism.

• Tuberculosis and Respiratory Diseases
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• v.59 no.3
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• pp.286-297
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• 2005

Background : Non-small cell lung cancer (NSCLC) is a common cause of cancer-related death in North America and Korea, with an overall 5-year survival rate of between 4 and 14%. The TNM staging system is the best prognostic index for operable NSCLC . However, epidermal growth factor receptor (EGFR), matrix metalloproteinase-9(MMP-9), and C-erbB-2 have all been implicated in the pathogenesis of NSCLC and might provide prognostic information. Methods : Immunohistochemical staining of 81 specimens from a resected primary non-small cell lung cancer was evaluated in order to determine the role of the biological markers on NSCLC . Immunohistochemical staining for EGFR, MMP-9, and C-erbB-2 was performed on paraffin-embedded tissue sections to observe the expression pattern according to the pathologic type and surgical staging. The correlations between the expression of each biological marker and the survival time was determined. Results : When positive immunohistochemical staining was defined as the extent area>20%(more than Grade 2), the positive rates for EGFR, MMP-9, and C-erbB-2 staining were 71.6%, 44.3%, and 24.1% of the 81 patients, respectively. The positive rates of EGFR and MMP-9 stain for NSCLC according to the surgical stages I, II, and IIIa were 75.0% and 41.7%, 66.7% and 47.6%, and 76.9% and 46.2%, respectively. The median survival time of the EGFR(-) group, 71.8 months, was significantly longer than that of the EGFR(+) group, 33.5 months.(p=0.018, Kaplan-Meier Method, log-rank test).. The MMP-9(+) group had a shorter median survival time than the MMP-9(-) group, 35.0 and 65.3 months, respectively (p=0.2). The co-expression of EGFR and MMP-9 was associated with a worse prognosis with a median survival time of 26.9 months, when compared with the 77 months for both negative-expression groups (p=0.0023). There were no significant differences between the C-erbB-2(+) and C-erbB-2 (-) groups. Conclusion : In NSCLC, the expression of EGFR might be a prognostic factor, and the co-expression of EGFR and MMP-9 was found to be associated with a poor prognosis. However, C-erbB-2 expression had no prognostic significance.

• Tuberculosis and Respiratory Diseases
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• v.60 no.4
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• pp.451-463
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• 2006

Background : Reactive oxygen species (ROS) take center stage as executers in ventilator-induced lung injury (VILI). The protein with DNA-damage scanning activity, poly (ADP-ribose) polymerase-1 (PARP1), signals DNA rupture and participates in base-excision repair. Paradoxically,overactivation of PARP1 in response to massive genotoxic injury such as ROS can induce cell death through ${\beta}$ -nicotinamide adenine dinucleotide ($NAD^+$) depletion, resulting in inflammation. The purpose of this study is to investigate the role of PARP1 and the effect of its inhibitor in VILI. Methods : Forty-eight male C57BL/6 mice were divided into sham, lung protective ventilation(LPV), VILI, and PARP1 inhibitor (PJ34)+VILI (PJ34+VILI) groups. Mechanical ventilator setting for the LPV group was $PIP\;15cmH_2O$ + $PEEP\;3cmH_2O$ + RR 90/min + 2 hours. The VILI and PJ34+VILI groups were ventilated on a setting of $PIP\;40cmH_2O$ + $PEEP\;0cmH_2O$ + RR 90/min + 2 hours. As a PARP1 inhibitor for the PJ34+VILI group, 20 mg/Kg of PJ34 was treated intraperitoneally 2 hours before mechanical ventilation. Wet-to-dry weight ratio and acute lung injury (ALI) score were measured to determine the degree of VILI. PARP1 activity was evaluated by using an immunohistochemical method utilizing biotinylated NAD. Myeloperoxidase (MPO) activity and the concentration of inflammatory cytokines such as tumor necrosis factor $(TNF)-{\alpha}$, interleukin $(IL)-1{\beta}$, and IL-6 were measured in bronchoalveolar lavage fluid (BALF). Results : In the PJ34+VILI group, PJ34 pretreatment significantly reduced the degree of lung injury, compared with the VILI group (p<0.05). The number of cells expressing PARP1 activity was significantly increased in the VILI group, but significantly decreased in the PJ34+VILI group (p=0.001). In BALF, MPO activity, $TNF-{\alpha}$, $IL-1{\beta}$, and IL-6 were also significantly lower in the PJ34+VILI group (all, p<0.05). Conclusion : PARP1 overactivation plays a major role in the mechanism of VILI. PARP1 inhibitor prevents VILI, and decreases MPO activity and inflammatory cytokines.