Effect Of Combining Aerosolized Perfluorocarbon With Ambroxol In Rabbits With Acute Lung Injury

Acute lung injury (ALI)/acute respiratory distress syndrome(ARDS) are critical clinical syndrome consisting of acute hypoxemic respiratory failure with pulmonary infiltrates those are not attributed to cardiogenic pathogeny, and with the feature that dependent(dorsal) regions is worse than nondependent regions of lung. The mortality rate from acute lung injury and acute respiratory distress syndrome is approximately 40 to 50 percent. Although substantial progress has been made in elucidating the mechanisms of acute lung injury, there has been little progress in developing effective treatments.So far, mechanical ventilatory support is main treatment of ALI/ARDS. However, mechanical ventilation is likely to induce ventilator associated lung injury(VALI) during the initial stage of ALI, the current studies indicate repeated alveolar collapse and reopening result in the lung injury. The lung protective ventilation strategy(permissive hypercapnia) can improve arterial oxygen tension(PaO₂) and prevent VALI. It is the first time that a therapy has been shown to reduce mortality in patients with ALI/ARDS. However the mortality is still high, the search of potential new effective therapies is very important.Partial liquid ventilation by perfluorocarbon(PFC) has been widely used. Kandler et al. recently demonstrated better gas exchange that was sustained for a longer period in ALI when a perfluorocarbon was aerosolized. Additionally, mucosulvan(ambroxol), a mucolytic agent, can suppress the production of free radicals, and stimulate secretion of pulmonary surfactant. Ambroxol is known to behave as an antioxidant agent. We established rabbit model with ALI by injecting oleic acid. Subsequently we examined the impact of combining aerosolized perfluorocarbon with ambroxol on oxygenation, the expression of cytokine, the pathology, the malondialdehyde(MDA) and pulmonary static compliance(CLst) to discuss the potential role and cooperativity of these treatments.Methods: (1) the first part of this experiment: rabbit model with ALI was established by injecting oleic acid(International Laboratory Limited Company,Purity:95%)(0.15～0.18)ml/kg; (2) Thirty-two oleic acid-induced ALI rabbits were divided into four groups: CMV group(group A) received conventional mechanical ventilation; Rabbits in the Aerosol-PFC group(group B) received 6mL/(kg·h) aerosolized perfluorocarbon(PFC, FC-77, 3M, USA); Rabbits in the Aerosol-mucosulvan group(group C) received 15mg/(kg·h) aerosolized mucosulvan; United group(group D) was aerosolized perfluorocarbon and mucosulvan. In all animals, respiratory support was held constantly at identical respiratory settings. The changes of gas exchange and static lung compliance(CLst) were examined before ALI, during ALI and at 1, 2, 3, 4h after treatment. Histological sections taken from dependent(dorsal) and nondependent regions of lung were stained by H & E. The express of TNF-αmRNA in dependent(dorsal) and nondependent regions of lung were detected by in situ hybridization(ISH).Malonaldehyde(MDA) levels in lung homogenate were determined by the thiobarbituric acid(TBA) reaction.Results: (1) After hurted, the level of CLst showed progressive decrease in the group A. The CLst levels in group B and D showed progressive increase, and were significantly higher than those in group A at 1 h～3 h after treatment ( P < 0.05). The CLst levels in group B were significantly higher than those in group A and C at 1 h～2 h after treatment. The CLst levels in group D were significantly higher than those in group A and the C at 1 h～3 h after treatment. There was no difference in CLst levels between group A and group C. (2) The at 1 h～4 h after treatment were higher than the PaO₂ levels during ALI in group B and D. The PaO₂ levels in group B and D were significantly higher than those in group A and C at 1 h～3 h after treatment(P < 0.05). There was no difference in PaO₂ levels between the A group and the C group. (3) The tissue damage of lung in group B and D were less severe than that in group A. In all groups, the tissue damage of gravity dependent (dorsal) regions was more severe than nondependent regions of lung. (4) The expression of TNF-αmRNA was detected by in situ hybridization(ISH). Regarding TNF-αmRNA, group B and D showed significantly lower expression than group A did, group D showed lower expression than group B did in dependence(dorsal) regions and nondependent regions of lung. In all groups, the nondependent regions of lung showed lower expression than the gravity dependence(dorsal) regions did. (5) Malonaldehyde(MDA) levels in lung homogenate were determined by the thiobarbituric acid(TBA) reaction, malonaldehyde(MDA) level in group D was lower than the other groups,. The group B showed lower MDA level than group A and C did(P<0.05). There was no significant difference in MDA level between group A and group C (P >0.05).Conclusion: (1) Aerosolized perfluorocarbon (PFC) can improve the oxygenation and CLst, increase the PaO₂, decrease the expression of tumor necrosis factor-αmRNA, and attenuate the injury of free radical in the lung; (2) The combination of aerosolized perfluorocarbon (PFC) with ambroxol can decrease the expression of tumor necrosis factor-αmRNA, attenuate the injury of free radical in the lung, improve the CLst and oxygenation of lung, and increase the PaO₂ during acute lung injury. The combination of aerosolized perfluorocarbon (PFC) with ambroxol show cooperativity in decreasing the expression of tumor necrosis factor-αmRNA and attenuate the injury of free radical; (3) In all groups, the tissue damage of gravity dependence(dorsal) regions is worse than nondependent regions of lung. Regarding TNF-αmRNA, the nondependent regions of lung show lower expression than the gravity dependence(dorsal) regions did .