Protective Effect And Mechanism Of α-melanocyte Stimulating Hormone On The Two-hit ARDS Rat Model

Objective: To investigate the protective effect ofα-melanocyte stimulating hormone(α-MSH)on ARDS rats with acute hemorrhagic shock and sequentially administered endotoxin intratracheally (two-hit) and its mechanism. Methods: Thirty male Sprague Dawley rats, weight 337±25g, were randomly assigned to six groups with 5 each group. Group A was normal and group B ARDS control. The treatment groups were divided into groups C～F according to the giving time of α-MSH (group C: givingα-MSH one hour before the challenge of LPS; group D: giving α-MSH and LPS simultaneously; group E: givingα-MSH one hour after the challenge of LPS; group F: givingα-MSH at the same time of LPS challenge and at third and sixth hour after the LPS challenge, respectively) . α-MSH 1.7 mg·kg-1 was intravenously administrated at each time point. All rats were anesthesized and ventilated mechanically with FiO2 0.5, BR 100·min-1, VT12ml·kg-1 and I/E 1/1.5. The blood was withdrawed to induce hemorrhagic shock via the carotid until blood pressure reached 45±5mmHg and lasted for 1 hour, and the shed blood and Ringer's lactate in volume equal to the shed blood were reinfused for resuscitation in two hours in groups B～F . Afterwards, LPS was given via the trachea(200μg·kg-1,in 500μl normal saline) to establish the ARDS model. The changes of the hemodynamics (MAP and HR) and the arterial blood gas analysis were monitored, the serum levels of cytokines (TNF-α,IL-1,IL-6,IL-10) and nitric oxide were measured at beginning of the experiment, challenge of LPS and each 3 hours following the challenge of LPS for 3 times. Thehistological changes of the heart, liver, lung, kidney and bowel and the ultrastructure of heart, liver and lung were observed .Results: No marked changes of the parameters were observed in group A(P>0.05), while the hemodynamics, blood gas analysis worsened dramatically (P<0.01), the pro/anti-inflammatory cytokine balance violated and the NO concentration increased in group B. No effect was observed in group E comparing with that in group B. Different protective effects were observed in group C, D and F with the best effect in group F. α-MSH could improve the changes of the hemodynamics and blood gas analysis, decrease the serum concentration of TNF-α, IL-1 and NO(P<0.01),increase the production of IL-6 and IL-10(P<0.01)and protect the heart, liver, lung, kidney and bowel in group C, D and F with the best effect in group F.Conclusion: α-MSH could stabilize the hemodynamic, improve the blood gas analysis decrease the concentration of the proinflam matory cytokines and NO , increase the production of the anti-inflammatory cytokines, and protect vital organs. α-MSH might play an important role in the therapy of ARDS, at least partially by modulating the cytokine balance.