Inter-cellular signal transduction by alveolar macrophages in acute lung injury

为了研究肺泡巨噬细胞(AM)在革兰氏阴性细菌感染后PMN初始募集中的作用，我们通过雾化吸入包裹克罗磷酸二钠的带负电荷的大分子寡层脂质体(Cl2MDP-脂质体)来耗尽啮齿动物的AM。这种方法可以清除超过95%的肺泡巨噬细胞，而不会造成肺损伤或中性粒细胞增多。耗尽AMS可减少大鼠铜绿假单胞菌肺炎的PMN初始募集和趋化因子的产生。为了进一步评价AM在小鼠急性和亚急性铜绿假单胞菌肺炎中的作用，比较了AM耗竭小鼠和对照组小鼠经气管内感染铜绿假单胞菌后的变化。除了监测中性粒细胞的招募和趋化因子的释放外，还在感染后不久(8h)和随后的时间(48h)评估肺损伤。在8h，肺泡巨噬细胞耗尽减少了中性粒细胞的聚集、趋化因子的释放和肺损伤。然而，在48小时，肺泡巨噬细胞的耗尽降低了细菌的清除，并导致中性粒细胞从炎症部位延迟移动，从而加重了肺损伤。在对照组小鼠注射致死量为50%的条件下，AM耗竭小鼠在感染后24小时内的存活率较低，但死亡率较高。与未耗尽AM的小鼠相比，在稍后的时间。这些结果表明，肺泡巨噬细胞耗竭对铜绿假单胞菌肺炎的肺损伤和存活率有早期有益的影响，但对后期的影响是有害的。

To examine the role of alveolar macrophages (AMs) in initial PMN recruitment after Gram-negative bacterial infection, we depleted AMs in rodent by aerosol inhalation of negatively charged large oligolamellar liposomes encapsulating clodronate disodium (Cl2MDP-liposomes). This method cleared over 95% of AMs from the lungs without causing lung damage or airspace neutrophilia. Depletion of AMS attenuated initial PMN recruitment and chemokine production in Pseudomonas aeruginosa pneumonia in rats. To further evaluate the role of AMs in acute and subacute Pseudomonas aeruginosa pneumonia in mice, AM-depleted mice and control mice were compared after intratracheally infected by P. aeruginosa. In addition to monitoring neutrophils recrutiment and chemokine releases, lung injury was evaluated soon after infection (8 h) and a later time (48 h). At 8 h, depletion of AMs reduced neutrophils recrutiment, chemokine release and lung injury. At 48 h, however, depletion of AMs decreased bacterial clearance and resulted in delayed movement of neutrophils from the site of inflammation with aggravated lung injury. In the setting of 50% lethal amount of bacteria instillation in control mice, the survival rate of AM-depleted mice showed low mortality within 24 h of infecton, but high mortality. at later time in contrast to non-AM-depleted mice. These results demonstrate that depletion of AMs has beneficial early effects but deleterious late effects on lung injury and survival in P. aeruginosa pneumonia.