The Protective Effect Of Ambroxol Hydrochloride On Increased Vascular Permeability Induced By Inflammation

The vascular endothelial barrier is an important structure to maintain the exchange of nutrients in the blood and tissue,and the increased permeability caused by the destruction of the barrier are one of the most common pathological changes in the clinical practice,such as sepsis/SIRS and other inflammatory reactions,ischemia reperfusion injury,tumor with neovascularization and idiopathic diseases: systemic capillary leakage syndrome.At present,the mechanism of vascular permeability change is still not very clear.The main points are as follows: leakage of leukocyte from the blood,damage of vascular endothelial cells and vascular smooth muscle,blood pressure,flow velocity and shear stress in the blood vessel,and effective filtration pressure and lymphatic circulation disorder.Symptomatic treatment is the primary principle,so novel therapies and drugs are essential for the treatment of patient with increased vascular permeability.Ambroxol hydrochloride is a kind of adhesive lysing agent which is widely used in clinical practice.It can promote the secretion of pulmonary surfactant and tracheal glands,it also can increase the ciliary movement and reduce the viscosity of sputum,making it easy to cough up.At present,it is widely used in the treatment of chronic obstructive pulmonary disease,the treatment of the pulmonary diseases in neonates and premature infants,and the prevention of pulmonary complications after surgery in elderly patients.While,it has been reported that Ambroxol hydrochloride can effectively prevent the occurrence of neonatal respiratory distress syndrome and have a certain degree of protective effect of lung injury.And in clinical practice,it is found that ambroxol hydrochloride can relieve the condition and edema in ICU patients.However,the definite protective effects of ambroxol hydrochloride on the vascular permeability and possible mechanisms of the therapeutic effects has not been systemically elucidated.In the present experiments,the xylene induced auricle acute inflammation model and cecum ligation puncture induced acute lung injury model were established first,and then the effects and the possible molecular mechanism of ambroxol hydrochloride on the vascular permeability were observed.Objective: The purpose of this study was to observe the increased vascular permeability in several different pathological conditions,and to explore the protective effect of ambroxol hydrochloride on several conditions of induced vascular permeability increase;and provide some new references on the clinical application of ambroxol hydrochloride.Methods: Two animal models were used to carry out this research task: 1.In the model of mouse auricle skin inflammation,a mouse auricle inflammation model was established by smearing the auricle skin of mice with xylene.The mice were divided into two groups,the first group(saline control group)and the second group(ambroxol hydrochloride group),which were injected with the same volume of saline or ambroxol hydrochloride solution,and then detected the Evans Blue which were exudate from auricle.2.In the model of sepsis,the cecum of the mouse was ligated and puncture was performed at the end to establish a sepsis model in the mouse.The mice were divided into three groups,the first group(blank control group),the second group(saline control group),the third group(ambroxol hydrochloride group),the mice from the saline control group and the ambroxol hydrochloride group were injected with the same volume of saline and ambroxol hydrochloride solution.Detect the protein concentration of bronchial lavage fluid,the number of cells in bronchial lavage fluid,the dry-to-wet weight ratio of lung,the content of IL-1β in serum,the content of IL-6 in serum,the pathological section of HE staining.Results: 1.In the model of mouse auricle skin inflammation,there is a significant difference between the saline control group and the ambroxol hydrochloride group.It was found by gross photo observation that the exudation of Evans Blue in the auricle of mice injected with ambroxol hydrochloride was much lower than that of the auricle Evans Blue in the saline control group.The gray value of the auricle tissue showed that the gray value difference of the left and right auricles of the mice in the ambroxol hydrochloride group was higher than that of the saline control group(P=0.02).The calculation of OD value after auricle tissue grinding showed that the OD value of mouse auricle tissue of ambroxol hydrochloride group was lower than that of mouse auricle tissue of saline control group(P=0.002).2.In the model of septic mice,the injection of ambroxol hydrochloride also greatly reduced the inflammatory exudation of mice.In the pathological sections of HE-stained mouse lungs,it was observed that the lung tissue structure of mice in the ambroxol hydrochloride group was more complete and the number of inflammatory cells was less,while the lung tissue of the saline control group was more damaged.It is full of inflammatory cells.The mouse bronchial lavage fluid of the ambroxol hydrochloride group contained less protein than the saline control group by the protein concentration in the mouse bronchial lavage fluid(P=0.015),and contained fewer cells than the saline control group(P=0.04).By detecting inflammatory factors in mouse serum,it was found that mice injected with ambroxol hydrochloride contained less inflammatory factors: IL6(P=0.04),IL-1β(P=0.025).By calculating the dry-to-wet specific gravity of the mouse lung,it was found that the mouse lung of the ambroxol hydrochloride group contained less fluid exudation than the lung of the saline control group(P=0.017).The number of deaths in the ambroxol hydrochloride group was lower than that in the saline control group.Conclusions: 1.Auricular skin inflammation model mice will reduce the exudation of local inflammation when injected with ambroxol hydrochloride,suggesting that the injection of ambroxol hydrochloride may reduce the vascular endothelium in the inflammation site and reduce the leakage of fluid.2.Sepsis model mice will reduce inflammatory factor exudation and reduce protein and fluid exudation when injected with ambroxol hydrochloride,suggesting that the injection of ambroxol hydrochloride may diminish the gap in the vascular endothelium during sepsis and provide a protective effect.3.The mortality of mice in sepsis model after injection of ambroxol hydrochloride decreased,suggesting that the injection of ambroxol hydrochloride may affect the survival rate in sepsis.