• Applied Microscopy
• /
• v.33 no.1
• /
• pp.1-16
• /
• 2003

As is well known that N-nitroso-N-methylurethane (NNNMU) causes acute lung injury (ALI) in experimental animals. And ALI caused by NNNMU is very similar to ARDS in human being in its pathology and progress. In its context, we investigated the pathogenetic mechanism of ARDS associated with oxidative stress by neutrophils in Sprague-Dawley rat model of NNNMU-induced ALI. NNNMU had increased lung weight/body weight ratio (L/B ratio), lung myeloperoxidase (MPO) activity, protein content and number of neutrophils in bronchoalveolar fluid (BALF) compared with those of control rat (p<0.001, respectively). In contrast, the amount of pulmonary surfactant in BALF was decreased by NNNMU (p<0.001). Morphologically, light microscopic examination denoted pathological findings such as formation of hyaline membrane, infiltration of neutrophils and perivascular cuffing in the lungs of NNNMU-treated rats. In addition, ultrastructural changes such as the necrosis of endothelial cells, swelling and vacuolization of lamellar bodies of alveolar type II cells, and the degeneration of pulmonary surfactant were identified after treatment of NNNMU. Very interestingly, cerium chloride electron microscopic cytochemistry showed that NNNMU had increased the production of cerrous-peroxide granules in the lung, which signified the increased production of hydrogen peroxide in the lung. Collectively, we conclude that NNNMU causes acute lung leak by the mechanism of neutrophilic oxidative stress of the lung.

• Tuberculosis and Respiratory Diseases
• /
• v.51 no.6
• /
• pp.503-516
• /
• 2001

Background : The present study was carried out in association with neutrophilic respiratory burst in the lung in order to clarify the pathogenesis of acute respiratory distress syndrome(ARDS) following acute severe hemorrhage. Because oxidative stress has been suggested as one of the principal factors causing tissue injury, the role of free radicals from neutrophils was assessed in acute hemorrhage-induced lung injury. Method : In Sprague-Dawley rats, hemorrhagic shock was induced by withdrawing blood(20 ml/kg of B.W) for 5 min and the hypotensive state was sustained for 60 min. To determine the mechanism and role of oxidative stress associated with phospholipase A2(PLA2) by neutrophils, the level of lung leakage, pulmonary myeloperoxidase(MPO), and the pulmonary PLA2 were measured. In addition, the production of free radicals was assessed in isolated neutrophils by cytochemical electron microscopy in the lung. Results : In hypotensive shock-induced acute lung injury, the pulmonary MPO, the level of lung leakage and the production of free radicals were higher. The inhibition of PLA2 with mepacrine decreased the pulmonary MPO, level of lung leakage and the production of free radicals from neutrophils. Conclusion : A. neutrophilic respiratory burst is responsible for the oxidative stress causing acute lung injury followed by acute, severe hemorrhage. PLA2 activation is the principal cause of this oxidative stress.

• IMMUNE NETWORK
• /
• v.22 no.2
• /
• pp.18.1-18.15
• /
• 2022

Dysfunction of mitochondrial metabolism is implicated in cellular injury and cell death. While mitochondrial dysfunction is associated with lung injury by lung inflammation, the mechanism by which the impairment of mitochondrial ATP synthesis regulates necroptosis during acute lung injury (ALI) by lung inflammation is unclear. Here, we showed that the impairment of mitochondrial ATP synthesis induces receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis during lung injury by lung inflammation. We found that the impairment of mitochondrial ATP synthesis by oligomycin, an inhibitor of ATP synthase, resulted in increased lung injury and RIPK3 levels in lung tissues during lung inflammation by LPS in mice. The elevated RIPK3 and RIPK3 phosphorylation levels by oligomycin resulted in high mixed lineage kinase domain-like (MLKL) phosphorylation, the terminal molecule in necroptotic cell death pathway, in lung epithelial cells during lung inflammation. Moreover, the levels of protein in bronchoalveolar lavage fluid (BALF) were increased by the activation of necroptosis via oligomycin during lung inflammation. Furthermore, the levels of ATP5A, a catalytic subunit of the mitochondrial ATP synthase complex for ATP synthesis, were reduced in lung epithelial cells of lung tissues from patients with acute respiratory distress syndrome (ARDS), the most severe form of ALI. The levels of RIPK3, RIPK3 phosphorylation and MLKL phosphorylation were elevated in lung epithelial cells in patients with ARDS. Our results suggest that the impairment of mitochondrial ATP synthesis induces RIPK3-dependent necroptosis in lung epithelial cells during lung injury by lung inflammation.

• International Journal of Stem Cells
• /
• v.16 no.2
• /
• pp.191-201
• /
• 2023

Background and Objectives: O-cyclic phytosphingosine-1-phosphate (cP1P) is a synthetic chemical and has a structure like sphingosine-1-phosphate (S1P). S1P is known to promote cell migration, invasion, proliferation, and anti-apoptosis through hippocampal signals. However, S1P mediated cellular-, molecular mechanism is still remained in the lung. Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are characterized by excessive immune response, increased vascular permeability, alveolar-peritoneal barrier collapse, and edema. In this study, we determined whether cP1P primed human dermal derived mesenchymal stem cells (hdMSCs) ameliorate lung injury and its therapeutic pathway in ALI mice. Methods and Results: cP1P treatment significantly stimulated MSC migration and invasion ability. In cytokine array, secretion of vascular-related factors was increased in cP1P primed hdMSCs (hdMSC^cP1P), and cP1P treatment induced inhibition of Lats while increased phosphorylation of Yap. We next determined whether hdMSC^cP1P reduce inflammatory response in LPS exposed mice. hdMSC^cP1P further decreased infiltration of macrophage and neutrophil, and release of TNF-α, IL-1β, and IL-6 were reduced rather than naïve hdMSC treatment. In addition, phosphorylation of STAT1 and expression of iNOS were significantly decreased in the lungs of MSC^cP1P treated mice. Conclusions: Taken together, these data suggest that cP1P treatment enhances hdMSC migration in regulation of Hippo signaling and MSC^cP1P provide a therapeutic potential for ALI/ARDS treatment.

• Tuberculosis and Respiratory Diseases
• /
• v.45 no.1
• /
• pp.140-152
• /
• 1998

Background: Prone position improves oxygenation in patients with ARDS probably by reducing shunt Reduction of shunt in prone position is thought to be effected by lowering of the critical opening pressure (COP) of the dorsal lung because the pleural pressure becomes less positive in prone position compared to supine position. It can then be assumed that prone position would bring about greater improvement in oxygenation when PEEP applied in supine position is just beneath COP than when PEEP is above COP. Hemodynamically, prone position is expected to attenuate the lifting of cardiac fossa induced by PEEP. Based on these backgrounds, we investigated whether the effect of prone position on oxygenation differs in magnitude according to the level of PEEP applied in supine position, and whether impaired cardiac output in supine position by PEEP can be restored in prone position. Methods: In seven mongrel dogs, $PaO_2/F_1O_2$(P/F) was measured in supine position and at prone position 30 min. Cardiac output (CO), stroke volume (SV), pulse rate (PR), and pulmonary artery occlusion pressure (PAOP) were measured in supine position, at prone position 5 min, and at prone position 30 min. After ARDS was established with warmed saline lavage(P/F ratio $134{\pm}72$ mm Hg), inflection point was measured by constant flow method($6.6{\pm}1.4cm$ $H_2O$), and the above variables were measured in supine and prone positions under the application of Low PEEP($5.0{\pm}1.2cm$ $H_2O$), and Optimal PEEP($9.0{\pm}1.2cm$ $H_2O$)(2 cm $H_2O$ below and above the inflection point, respectively) consecutively. Results : P/F ratio in supine position was $195{\pm}112$ mm Hg at Low PEEP and $466{\pm}63$ mm Hg at Optimal PEEP(p=0.003). Net increase of P/F ratio at prone position 30 min, however, was far greater at Low PEEP($205{\pm}90$ mm Hg) than at Optimal PEEP($33{\pm}33$ mm Hg)(p=0.009). Compared to CO in supine position at Optimal PEEP($2.4{\pm}0.5$ L/min), CO in prone improved to $3.4{\pm}0.6$ L/min at prone position 5 min (p=0.0180) and $3.6{\pm}0.7$ L/min at prone position 30 min (p=0.0180). Improvement in CO was attributable to the increase in SV: $14{\pm}2$ ml in supine position, $20{\pm}2$ ml at prone position 5 min (p=0.0180), and $21{\pm}2$ ml at prone position 30 min (p=0.0180), but not to change in PR or PAOP. When the dogs were turned to supine position again, MAP ($92{\pm}23$ mm Hg, p=0.009), CO ($2.4{\pm}0.5$ L/min, p=0.0277) and SV ($14{\pm}1$ ml, p=0.0277) were all decreased compared to prone position 30 min. Conclusion: Prone position in a dog with saline-lavaged acute lung injury appeared to augment the effect of relatively low PEEP on oxygenation, and also attenuate the adverse hemodynamic effect of relatively high PEEP. These findings suggest that a PEEP lower than Optimal PEEP can be adopted in prone position to achieve the goal of alveolar recruitment in ARDS avoiding the hemodynamic complications of a higher PEEP at the same time.

• Journal of Chest Surgery
• /
• v.21 no.3
• /
• pp.471-478
• /
• 1988

We evaluated forty cases of traumatic diaphragmatic injuries that we have experienced from Jan. 1972 to Dec. 1987. 28 patients were male and 12 were female[M:F=2.3:1]. The age distribution was ranged from 4 to 71 years with mean age of 26. The diaphragmatic injuries were due to blunt trauma in 27 cases[traffic accident 22, fall down 3, others 2] and penetrating trauma in 13 cases[stab wound 11, gun shot 1, other 1]. In the blunt injury,14 cases of 17 were diagnosed and treated within 24 hours in the left diaphragmatic injury but only 3 cases of 7 cases in the right diaphragmatic injury were diagnosed and treated within 24 hours. All cases except one in penetrating injury were diagnosed and treated within 12 hours. In the blunt injury, the rupture site was located in the left in \ulcorner7 cases and in the right in 7 cases. In the penetrating injury, the rupture site was located in the left in 11 cases and in the right in 2 cases. The repair of 37 cases were performed with thoracic approach in 20 cases, thoracoabdominal approach in 12 cases and abdominal approach in 5 cases. Over all mortality was 17.5%[7/40] and postoperative mortality was 11%[4/37]. The causes of death were hypovolemic shock[3], combined head injury[2], acute renal failure[1] and septic shock with ARDS[1].

• Journal of Chest Surgery
• /
• v.27 no.10
• /
• pp.850-853
• /
• 1994

Open lung biopsy was performed in thirty patients for the diagnosis and staging evaluation of interstitial lung disease during the period from January 1987 until December 1992. The age of the patients ranged from 14 to 71 years [mean 48 years], and the patients consisted of 14 males and 16 females. Preoperative FEV1`s were from 0.80 liter to 3.88 liters [mean 1.66]. Other non-invasive diagnostic studies such as PCNA, bronchoalveolar lavage, TBLB, and gallium scan were also done in addition to X-ray and high-resolution chest CT. Tweaty-eight were correctly diagnosed and 2 cases were not [diagnostic yield rate 93.3%]. Among the 28 cases,pathologic diagnosis influenced further treatment regimens and prognostic expectations in 23 cases [82.1%]. The diagnostic non-invasive studies other than open lung biopsy yielded a correct diagnosis without staging only in 5 cases. There was no mortality and only one complication, ARDS ; however, the patient recovered after 5 days ventilator support. Open lung biopsy, which is the gold standard for the diagnosis and staging evaluation of interstitial lung disease can be done safely and has value in clinical decision making. Also knowledge of the involvement of the lesion is important for proper selection of the biopsy site.

• International Journal of Vascular Biomedical Engineering
• /
• v.4 no.1
• /
• pp.9-16
• /
• 2006

In this article we introduce computer models that have been developed in the past to determine the concentration of metabolic gases, the oxygen and carbon dioxide, along the pulmonary circulation. The terminal concentration of these gases in the arterial blood is related with the total change of the partial pressure of the same gases in the alveoli for the time beginning with inspiration and ending with expiration. It is affected not only by the ventilation-perfusion ratio and the gas diffusion capacity of the lung membrane but also by the pulmonary defect such as shunt, dead space, diffusion impairment and ventilation-perfusion mismatch. Some pathological pulmonary symptoms such as ARDS and CDPD can be understood through the mathematical models of these pulmonary dysfunctions. Quantitative study on the blood oxygenation process using various computer models is therefore of foremost importance in order to monitor not only the pulmonary health but also the cardiac output and cell metabolism. Reviewed in this paper include the basic and advanced methods that enable numerical study on the gas exchange and on the arterial oxygenation process, which might depend on the various heart and lung physiological conditions listed above.

• Journal of Trauma and Injury
• /
• v.28 no.1
• /
• pp.34-38
• /
• 2015

The case of a patient with a transfusion-related acute lung injury (TRALI) to whom extracorporeal membrane oxygenation (ECMO) had been applied is reported. A 55-year-old male injured with liver laceration (grade 3) without chest injury after car accident. He received lots of blood transfusion and underwent damage control abdominal surgery. In the immediate postoperative period, he suffered from severe hypoxia and respiratory acidosis despite of vigorous management such as 100% oxygen with mechanical ventilation, high PEEP and muscle relaxant. Finally, ECMO was applied to the patients as a last resort. Aggressive treatment with ECMO improved the oxygenation and reduced the acidosis. Unfortunately, the patient died of liver failure and infection. TRALI is a part of acute respiratory distress syndrome (ARDS). The use of ECMO for TRALI induced severe hypoxemia might be a useful option for providing time to allow the injured lung to recover.

• Journal of Chest Surgery
• /
• v.28 no.6
• /
• pp.601-605
• /
• 1995

Clinical evaluations were performed on 54 cases of the traumatic sternal fracture, those were admitted and treated at the department of Thoracic and Cardiovascular Surgery in Chosun University Hospital during the past 5 years period from January 1990 to December 1994. The frequency was about 7.8% of the nonpenetrating chest trauma. The ratio of male to female was 2 : 1 in male predominance. Average age was 45.7 years old and age distribution was from 18 to 80 years old. The most common cause in the sternal fracture were high decelerating injury[ 38 cases . The most common fracture site was sternal body. Associated intrathoracic organ injuries were cardiac contusion[11cases , hemopneumothorax and pulmonary contusion. Added, thoracic cage and extrathoracic organ injuries were rib fracture, head injuries, thoracic spinal fracture and long bone fracture. Abnormal ECG findings were sinus bradycardia[4 cases , sinus tachycardia[3 cases , bundle branch block, atrial fibrillaton, left ventricular hypertrophy and myocardial ischemia. The average days of admission was 19.1 days. All patients were treated with conservative treatment. The complications after treatment were atelectasis[2 cases ,empyema[1 cases , ARDS[1 cases .