The Role Of CXCR4 In The Mechanism Of Lung Injury Induced By Pulmonary Oxygen Toxicity

In diving operation and hyperbaric oxygen treatment,lung pathological changes and symptoms induced by high oxygen partial pressure or long time of oxygen inhalation are called pulmonary oxygen toxicity. Symptoms of pulmonary oxygen toxicity can be concealed by the nervous system symptoms of cerebral oxygen toxicity and the pathogenesis of pulmonary oxygen toxicity is unclear. The same goes for the effective intervention measures. If the treatment is not prompt, the patient may enters multi-system organ failure state once he evolves into acute lung injury and even respiratory distress syndrome. The prognosis for them is not so good.When pulmonary oxygen toxicity occurs, alveolar-capillary barrier is destroyed and gas exchange is compromised. Pulmonary inflammatory and edema occur simultaneously.With proinflammatory factors and chemokines, a large number of inflammatory cells raise into the lungs, not only damage endothelial barrier, also release a lot of materials such as protease, further aggravating inflammation in the lungs and epithelial cell damage, which induced more signal transduction pathways and the activation of transcription factors, formed the so-called " cascade amplification" effect.The severity of lung injury is linked to the inflammatory cells infiltration, and inflammatory cells infiltration is related to the chemotactic capability. Consequently, how to reduce inflammation cell chemotaxis ability and pulmonary inflammatory response and regulating signal transduction pathways have become an important target fo therapy in the lung injury when pulmonary oxygen poisoning occurs.CXCR4 belongs to G protein coupled receptor protein superfamily. In the process of inflammation and causative agent, CXCR4 can regulate cell signal transduction, induce inflammatory cells chemotaxis, and play an important role in maintaining inflammatory cells for dynamic balance. Earlier studies have found that rat lung tissue appeared haemorrhage and oedema after hyperbaric oxygen exposure.CXCR4 expression increased at the same time.We guess that the possible mechanism is that CXCR4 is activated by G protein coupled signaling pathways and related transcription factors cause cellular damage and apoptosis when vascular endothelial cells and alveolar epithelial cell injury.Then the tissue releases a series of inflammatory factor which cause further damage to the lung tissue. But the mechanism of the damage and related signal transduction pathways especially downstream inflammatory factors and the role of CXCR4 are not very clear.Consequently, the following studies were performed:1.The changes of CXCR4 expression in lung injury caused by pulmonary oxygen toxicity: We duplicated the animal model by 0.23 Mpa hyperbaric oxygen exposure and observed pathology change in the rat lung tissue under different exposure time.Lung wet/dry ratio and total protein in BALF could indicate permeability changes. CXCR4 expression of lung tissue is detected by Western Blot analysis and inflammatory factor TNF alpha, IL-1 beta are detected by ELISA as a measure of the downstream inflammatory factors level to explore how lung injury changes with time under hyperbaric oxygen exposure. The correlation analysis of lung wet/dry ratio,total protein in BALF,TNF- alpha,IL-1beta, CXCR4 and UPTD was performed to investigate the mechanism of CXCR4 change with lung injury.2. Intervention of CXCR4 antagonist in lung injury induced by pulmonary oxygen toxicity: According to preliminary results, the rats were pretreated with the CXCR4 antagonist AMD3100 and exposed to 0.23 MPa oxygen for 8 hours. We observed pathology change, lung permeability and CXCR4 expression in the rat lung tissue to estimate intervention of CXCR4 antagonist in lung injury caused by pulmonary oxygen toxicity. TNF alpha, IL-1 beta and caspase3 expression of lung tissue were detected to observe variation of downstream signaling pathway under the intervention of inhibitors. Consequently we can explore intervention of CXCR4 antagonist in lung injury caused by pulmonary oxygen toxicity further.The main results were as follows:1. The subject successfully duplicated the pulmonary oxygen toxicity rat model by 0.23 MPa hyperbaric oxygen exposure with different duration. The foundation for experiment was laid for the next step of the work.2. Lung pathology change and permeability gradually increase with the extension of hyperbaric oxygen exposure time and lung tissue damage. CXCR4 expression of lung tissue after hyperbaric oxygen exposure significantly increased(P < 0.01). It increased with the exposure time variety and reached a peak in group 8 hours. Contents of TNF alpha, beta, IL- 1 the same change trend wth CXCR4 expression. Rat lung wet/dry ratio, total protein in BALF, CXCR4 expression, the content of TNF alpha and IL- 1 beta after different hyperbaric oxygen exposure time were positively correlated with UPTD(P < 0.01).3. Compared with air PBS group, CXCR4 expression,TNF alpha, IL-1 beta and cleaved caspase3 expression in air AMD3100 group change with no significant difference(P > 0.05); After hyperbaric oxygen exposure, CXCR4 expression,TNF alpha, IL-1 beta and cleaved caspase3 expression in air AMD3100 group decreased with significant difference(P < 0.01). At the same time, rat lung tissue pathology and permeability were also reduced after the rats were pretreated with AMD3100. It indicates that AMD3100 can reduce the lung injury induced by pulmonary oxygen toxicity in rats. Targeted therapy of CXCR4 is much more specific and selective. It is worth for us to study further.In conclusion, the subject illustrates possible mechanism of CXCR4 in lung injury induced by pulmonary oxygen toxicity.It provides a new evidence to find target of interventions of lung injury induced by pulmonary oxygen toxicity.And it can provide effective medical security for diving operation and clinical treatment.