New strategies for the inhibition of Infection and Inflammation in Cystic Fibrosis Lung Disease

囊性纤维化是英国和世界范围内最常见的遗传性疾病之一。虽然许多器官参与了疾病的进展，但绝大多数患者将死于呼吸衰竭，原因是压倒性感染和过度炎症导致的肺组织破坏。目前，抗菌素被用来治疗肺部感染，妥布霉素(TOBI)已被成功地用于减少感染和改善肺功能。然而，尽管感染减少了，但由于Tobi无法穿透CF肺中存在的厚厚的分泌物(粘液和痰)，因此CF肺中的细菌数量仍然很高。此外，托比只会在肺部停留很短一段时间，然后才会被移出体内。另一种名为SLPI的药物此前曾用于治疗CF肺部疾病的临床试验。SLPI的作用是减轻CF肺中的炎症，炎症可能会损害肺组织。我们建议将Tobi与SLPI联系起来，以开发一种双基药物，能够更有效地对抗CF肺的炎症和感染。这种药物的SLPI部分将把Tobi带到CF肺的痰/粘液丰富的区域，在那里它将被切割出来，直接作用于它通常无法杀死的细菌。此外，我们最近发现SLPI本身会受到肺部炎症的损害，从而降低其有效性。我们建议制造一种更稳定的SLPI，这种SLPI不会在CF肺中受到损害，因此在减轻CF肺部炎症方面更有效。我们将把Tobi与这种新的SLPI变体联系起来，以制造一种双重基础药物。就其本身而言，新的SLPI变体将比天然SLPI更有效地抑制炎症。因此，这种联合的SLPI-TOBI药物应该更有效地减少CF肺的炎症和感染，从而稳定接受治疗的患者的肺功能。最终，我们希望SLPI-TOBI药物将成为治疗CF肺部疾病的主要疗法，并延长接受该药物的患者的生命。我们还预计SLPI-TOBI将用于其他慢性肺部疾病，如慢性阻塞性肺疾病，其特征也是过度炎症和感染。

Cystic Fibrosis (CF) is one of the most common genetically inherited illnesses in the UK and worldwide. Although a number of organs are involved in the disease progress the vast majority of individuals with the disease will die as a result of respiratory failure due to a combination of overwhelming infection and lung tissue destruction as a result of excessive inflammation. Currently, antibiotics are used to treat the infection in the CF lung and tobramycin (tobi) has been developed and used to successfully reduce infection and improve lung function. However, despite the reduction in infection, the number of bacteria still resident in the CF lung remains very high due to the inability of tobi to penetrate into the thick secretions (mucus and sputum) present in the CF lung. Also, tobi only remains in the lung for a short period of time before it is removed from the body. Another drug, called SLPI, has previously been used in clinical trials to treat CF lung disease. SLPI works to reduce the inflammation in the CF lung which can be damaging to lung tissue. We propose linking tobi to SLPI in order to develop a dual-based drug that will be able to combat inflammation and infection more effectively in the CF lung. The SLPI part of this drug will bring tobi to the sputum/mucus-rich areas of the CF lung where it will be cleaved off and act directly on bacteria that it would not normally be able to kill. In addition, we have recently shown that SLPI itself can be damaged by inflammation in the lung thus reducing its effectiveness. We propose making a more stable variety of SLPI that will not be damaged in the CF lung and therefore be more effective in decreasing CF lung inflammation. We will link tobi to this new SLPI variant to make a dual-based drug. For its part, the new SLPI variant will inhibit inflammation more effectively than native SLPI. Therefore, this combined SLPI-tobi drug should be more effective at reducing inflammation and infection in the CF lung and thus stabilise lung function in treated patients. Ultimately, we hope that the SLPI-tobi drug will be a mainstay therapy for the treatment of CF lung disease and prolong the lives of patients receiving it. We also envisage that SLPI-tobi will find use in other chronic lung diseases such as Chronic Obstructive Pulmonary Disease which is also characterised by excessive inflammation and infection.