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

囊性纤维化（CF）是英国和全球最常见的遗传性疾病之一。虽然许多器官参与疾病进展，但绝大多数患有该疾病的个体将由于过度炎症导致的压倒性感染和肺组织破坏的组合而死于呼吸衰竭。目前，抗生素被用于治疗CF肺中的感染，妥布霉素（妥布霉素）已被开发并用于成功减少感染和改善肺功能。然而，尽管感染减少，但由于细菌不能渗透到CF肺中存在的粘稠分泌物（粘液和痰）中，CF肺中仍然存在的细菌数量仍然非常高。此外，在从身体中取出之前，肺内的维生素A只会在肺中停留很短的时间。另一种名为SLPI的药物此前已用于治疗CF肺病的临床试验。SLPI可以减少CF肺中的炎症，这可能会损害肺组织。我们建议将SLPI与TBI连接起来，以开发一种能够在CF肺中更有效地对抗炎症和感染的双重药物。这种药物的SLPI部分将使Cefi进入CF肺的痰/粘液丰富区域，在那里它将被切割并直接作用于通常无法杀死的细菌。此外，我们最近已经表明，SLPI本身可以被肺部炎症破坏，从而降低其有效性。我们建议制备一种更稳定的SLPI，这种SLPI在CF肺中不会受损，因此在减少CF肺炎症方面更有效。我们将把Lepti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SLPI-LIPi药物应该更有效地减少CF肺中的炎症和感染，从而稳定治疗患者的肺功能。最终，我们希望SLPI-BRILI药物将成为治疗CF肺病的主要疗法，并延长接受它的患者的生命。我们还设想SLPI-BRILI将用于其他慢性肺病，如慢性阻塞性肺病，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.