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Reexpansion pulmonary edema (RPE) is a kind of pulmonary edema occurred in the process of lung re-expansion or after lung re-expansion, which is secondary to the pulmonary collapse due to various reasons. Unfortunately, RPE may lead to severe acute respiratory failure. It is likely to appear immediately after the lung re-expansion, most of which occurred no more than 2 hours after the pulmonary re-expansion. In the early stage, it appears as performance of drained gas, liquid, severe coughing, shortness of breath, chest pain, chest tightness, heart palpitations, restlessness, followed by coughing up a lot of white or pink Color foamy sputum. Severe shock and coma can occur in the worst conditions. Examination shows rapid breathing rate, severe cases, signs of hypoxia, increased heart rate, blisters appeared everywhere in the lesioned side of pulmonary, what is more, some patient can suffer from re-expansion hypotension. Under general anesthesia with mechanical ventilation, pulmonary edema often occurs immediately after surgery re-expansion end and about half an hour after operation. It is such an emergency and critical condition of serious anesthesia, surgical complications that the prognosis is disaster, ranging from postoperative patients Recovery delay to life-threatening, in the case failure to timely diagnosis and emergency treatment,It has been generally recognized as both pulmonary edema due to the increase of capillary permeability, which was caused by chronic lung collapse, and the mechanical stress, which is added to pulmonary capillary by reexpansion, are generally recognized as two major causes of RPE, the underlying mechanism is still an open question. Recently, it has been shown that there are more than one proposal: 1. mechanical stress:both the increase of space between capillary endothelial cell due to mechanical injury to capillary, which was caused by the rapidly reexpandig lung and the high pressure inside, and outflow of water, proteins and cellular component due to the increasing inside pressure caused by the reexpanding lung account for the mechanical stress.2. decrease of surface-active substrate of lung:the low acivity of alveolar epithelial typeⅡcells, injured by ischemia and anoxia after pulmonary collapse, produce less surface active substrate, leading to the increasing of surface tension of pulmonary alveoli, therefore, the higher pressure was needed to re-expand the collapsed lung, which may result in the formation of pulmonary edema from the outflow of water to the lung matrix and alveoli.3. reperfusion injury of pulmonary alveoli:ischemia reperfusion injury, caused by hypoxic contraction of lung vessels due to ischemia and anoxia, may produce lots of oxygen free radical, consequently resulting in the injure to pulmonary endothelial cells.4. inflammatory reaction:it is one of the most important component in the formation of RPE.The pathological changes of re-expansion pulmonary edema include various process, ranging from the increased capillary permeability, to neutrophil and mononuclear cell infiltration.As important components of inflammatory cytokines, both TNF-αand IL-8 play very citecal roles in the initiating and development of acute lung injury. TNF-αcan stimulate the synthesis and release of IL-8 from macrophage, Additionally, the binding between abnormal elevated TNF-αand TNF-αreceptor of lung tissue may lead to the lysosomal damage, which in turn can cause lung injury via enzyme leakage. TNF-αcan also stimulate and regulate blood vessel Endothelial cells, the net result of which is to increase the expression of vascular endothelial cell surface intercellular adhesion molecule-1 (ICAM-1), leading to the increase in adhesion between ICAM-1 and leukocyte.Therefore, with the help of the blood, TNF-αcan migrate to the inflammatory exudate parts, worsening the lung damage. Last but not the least, TNF-αcan also directly inhibit vascular endothelial Cell adhesion, promote thrombosis, and lead to ventilatory disorder, at last produce pulmonary edema.IL-8 is generally recognized as one of the various causes of inflammation in lung injury-specific factors. Because its main biological activity is to attract and activate neutrophils, IL-8 was also named as neutrophil activating peptide, granulocyte chemotactic peptide, and neutrophil activating factor as well. After exposure to IL-8, neutrophils experience morphological changes, then directedly migrate to the reaction site, where they release a series of active products. To achieve the purpose of cell damage, the body of these substances released from neutrophils can lead to local inflammatory reaction. IL-8 is one of the main chemokines, causing an exudate of recruited neutrophils to sites of inflammation, resulting in neutrophil accumulation and activation of a large number, finally producing the occurrence of inflammation and causing lung injury. TNF-αcan further amplify the inflammation Signal, the result of which is to produce the "cascade" effect, through the induction,production and release of other cytokines, such as 1L-1, IL-6, IL-8 etc, during the damage caused by the body, and the activation of inflammatory effector cells then release more inflammatory factors in turn. In a word, TNF-αis a good candidate to reflect the strength of acute lung injury and inflammation observed during treatment effect. That is to say, both TNF-αand IL-8 mediate the initiation and development of pulmonary inflammatory response in RPEIn the case of immediate intervention often in the treatment of their symptoms after a few hours to several days, the prognosis of RPE is optical, it may disappear, leaving no sequelae. However, if it is failed to receive timely medical treatment, RPE-induced pulmonary edema and hypoxemia may aggravate the injury, what is more, RPE even cause irreversible respiratory Distress syndrome and multiple pipe failure, leading to death finally, the mortality of which can be as high as 20%. With the increasing awareness of this disease, it is highly recommended that both early preconditioning-improving tissue perfasion and reducing inflammation to prevent its occurrence are very important measures for a relatively optical prognosis.Ulinastatin, which is extracted from the human urine, is an enzyme inhibitor with wide spectrum, inhibitoring various proteinase, sugar and hydrolase as well. Currently, its major application in use is to alleviate the inflammatory damage to the organs caused by acute pancreatitis, as well as the ischemic reperfusion injury during the extracorporeal circulation, because the Ulinastatin plays an important role in such processes as inhibiting activity of hydrolase, controlling excessive inflammatory reaction, improving organ blood flow, alleviating the damage of various protease and inflammatory factors to the cells and organs.It has been proofed that it has a role in the inflammatory factors of pulmonary inflammatory reaction during cardiac surgery. However, its therapeutic effects in the reexpansion pulmonary edema is still an open question.ObjectiveTo explore the effect of pre-treatment rabbit with ulinastatin on re-expansion pulmonary edema in the term of inflammatory response.Methods27 healthy male New Zealand white rabbits, body weight of which rang from 2.5 kg to 3.0 kg, were randomly divided into three groups:normal group (N group, n= 9), the rabbits of which were not received the lung collapse operation, instead 5min before the lung re-expansion,2ml/kg normal saline were injected to each subjects; the control group (C group, n=9), the rabbits in this group received 2ml/kg normal saline at the time point of 5min before the pulmonary re-expansion; ulinastatin group (Uti group, n=9), the rabbits of this group received ulinastatin 20000u/kg (10009u/ml) at the time point of 5min before the pulmonary re-expansion. It has been recommended that Sakao improved method was better for the establishment of re-expansion pulmonary edema model in rabbit, therefoe, fasting was applied for 6 hours before operation. At the first, intramuscular injection of atropine at the dose of 0.25mg, and ear vein injection of 2% sodium pentobarbita at the dose of 30mg/kg were performed. Secondly, the rabbit was fixed on the operating table in the supine position, then a little airbag was placed into the pleural intercostals between 3 and 4,at the right edge of the sternum. The airbag was injected gas (10ml/kg). Thirdly, the 7 line ligation was used to close the cuff mouth. At the last, the chest was closed with very careful to avoid any additional injure. After their return from anesthesia, the rabbit received operation was sent to cage immediately, intensive care were performed.7 days later, the rabbits received another treatment. After complete anesthesia, the little rabbits were operated on the following process:such as tracheotomy, intubation, and interspersed with isolated right carotid artery catheter, followed by connection to monitor arterial blood pressure monitor. Then, the three groups received different intervention. N group was given saline at the dose of 2.0 ml/kg, so was the rabbits of C group; Uti group was given ulinastatin at the dose of 20000 u/kg by the way of ear vein injection. About 5 min later, when vital signs were basically becoming stable, the air bags in the rabbits of both C group and Uti group were removed carefully, and instead chest tube suction line was placed, the suction pressure of which was set at minus 20cm H2O, and followed by bulge the lung with a simple drum lung ventilator at the total of 5 times at the condition of airway pressure ranging from 15 to 20 cm H2O, in order to promote lung re-expansion. Finally, chest tube was clamped, then removed it from the chest, and make the rabbit recover its spontaneous breathing air as soon as possible. A total of 3ml arterial blood was collected at three time points:before the pulmonary re-expansion (T1),30 min (T2),3 h after pulmonary re-expansion (T3), then the sample blood were separated into plasma, which was placed in -80°refrigerator for the later tests.5 h later, the animals were sacrificed. We dissected chest, observed the situation of lungs, and quickly took the same part of the lower lobe lung tissue in 10% formalin, then fixed the tissue in paraffin embedded, which underwent sliced and hematoxylin-eosin (HE) staining, followed by observasion under light microscope changes in lung pathology. Both plasma interleukin-8 (IL-8) and tumor necrosis factor (TNF-a) were measured by enzyme-linked immunosorbent assay (ELISA) method, according to the instructions.ResultsLung tissue specimens of N group were no gross abnormalities, in the addition, biopsy showed normal lung tissue under light microscope. However, the lung tissue specimens of both C group and Uti group showed the right lung color red, and slightly heavier than the left lung, the volume increased significantly, compared with the gross, and the right Lung tissue can be seen under the cut surface foam as well; under the light microscope, a large number of neutrophils and mononuclear cell were demonstrated infiltration, as well as interstitial and alveolar edema; in addition, in the comparison with the rabbits of C group, the rabbits in the Uti group, which underwent the injection of ulinastatin, both alveolar edema and pulmonary edema were improved significantly. Of course, both neutrophil infiltration and monocyte Cell infiltration were improved as well.The plasma levels of IL-8 in N, C and Uti group meet the spherically symmetric assumption (P=0.324) at each time point, using repeated measures analysis of variance (Tab.1-2). To test interaction effect between the experimental group and time statistically significant (F=12.89, P<0.001), shown in Figure 1-1, further analysis was applied to compare a separate effect. Differences in plasma levels of IL-8 were statistically significant (P<0.001) at (?)(?)ch time point in each experimental group. Pairwise comparison results showed that in three time points, plasma levels of IL-8 in N group were statistically lower than the other two ones (P<0.001), while no difference between Uti and C groups (P>0.05) (Tab.1-3). There was no significant differences in N group at three time points on the plasma levels of IL-8 (P=0.193); while difference between C group and Uti group on two of three time points were found (P<0.001, P=0.035). Pairwise comparison results also showed that the plasma levels of IL-8 in 30 min (T2) and 3h (T3) after lung recruitment in C group were significantly lower than that before reexpansion (T1) (P<0.001); while there was no significant difference in comparisons between T2 and T1,T3 and T1 in Uti group(Tab. 1-4)The plasma levels of TNF-αin N, C and Uti group do not satisfy t the spherically symmetric assumption (P=0.003) at each time point, therefore Greenhouse-Geisser correction method was applied (Tab.1-5). To test interaction effect between the experimental group and time statistically significant (F=31.77, P<0.001), shown in Figure 1-2, further analysis was applied to compare a separate effect. Differences in plasma levels of TNF-αwere statistically significant (P<0.001) at each time point in each experimental group. Pairwise comparison results showed that in three time points, plasma levels of TNF-αin N group were statistically lower than the other two ones (P<0.001), while no difference between Uti and C groups (P> 0.05) (Tab.1-5). There was no significant differences in N group at three time points on the plasma levels of TNF-α(P=0.829); while difference between C group and Uti group on two of three time points were found (P<0.001, P=0.022). Pairwise comparison results also showed that the plasma levels of TNF-a in 30 min (T2) and 3h (T3) after lung recruitment in C group were significantly higher than that before reexpansion (T1) (P <0.001); while there was no significant difference in comparisons between T2 and T1,T3 and T1 in Uti group(Tab.1-7).ConclusionThe balloon method can be successfully used to produce the re-expansion pulmonary edema model in the rabbit, and the rapid re-expansion of lung collapse can cause the IL-8 and TNF-αrelease and acute pulmonary edemain the rabbits. It plays an important role for UTI given before preconditioning in decreasing IL-8 and TNF-αrelease, reducing pulmonary edema, and thus it can play a protective role in acute lung tissues damage.
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