Resolution of inflammation in the human lung: Mechanisms involved in leukocyte egression across the alveolar and bronchial epithelium.

肺病是造成许多发病率和死亡率的原因，目前在欧洲有五分之一的人死于肺病。许多肺部疾病，包括慢性阻塞性气道疾病（COPD）、肺炎、流感和某些形式的肺纤维化（PF），都以肺部炎症为特征。白细胞（White blood cells，简称白细胞）在人体中不断流动，以防止感染，但白细胞数量过多会对肺部造成损害，在消除炎症的过程中，有效清除这些细胞至关重要。尽管我们对白细胞如何进入肺部了解甚多，但对于它们如何离开或在患者死亡时如何从肺部清除却知之甚少。我们已经证明，白细胞可以离开肺部，进入气道，在那里它们可以作为痰被咳嗽出来。然而，白细胞也可能进入肺的肺泡，在那里进行气体交换。如果不迅速清除，它们会使病人的病情恶化。我们的目标是了解白细胞进入气道或肺泡的调控机制。如果我们了解这一点，那么我们可能能够促进肺部炎症的解决，加速肺部疾病的恢复。我们发现肺细胞上叫做ICAM-1和ICAM-2的特定分子是白细胞进入肺不同部位所必需的，我们已经证明了其他叫做狭缝的蛋白质可以改变白细胞的迁移。我们还表明，ICAM-1和-2存在于气道之间和肺泡中的不同水平。此外，气道和肺泡之间的裂隙水平也不同。我们认为，关键粘附分子如ICAM-1和ICAM-2的差异表达和调控，以及狭缝，使白细胞定位于气道而不是肺泡。我们建议这种本地化促进炎症的解决，我们的项目将进一步研究这一点。我们的最终目标是开发新的药物来帮助肺部炎症患者康复。

Lung disease is responsible for much morbidity and mortality and currently kills 1 in 5 people in Europe. Many lung diseases including chronic obstructive airways disease (COPD), pneumonia, influenza, and some forms of pulmonary fibrosis (PF) are characterised by lung inflammation. White blood cells, or leukocytes, travel continuously throughout the body to protect against infection, but in excessive numbers they can result in damage to the lung, and it is essential that these cells are cleared efficiently during the resolution of inflammation. Although much is known of how leukocytes enter the lung, much less is known about how they leave or are cleared from the lung as a patient revoers. We have shown that leukocytes can leave the lung by passing into the airways where they can be coughed up, as phlegm. However, leukocytes may also pass into the alveoli of the lung where gas exchange takes place. If they are not removed quickly they can worsen the condition of the patient. We are aiming to understand what regulations this leukocyte egression into the airways or into the alveoli. If we understand this then we may be able to promote the resolution of lung inflammation and speed the recovery from lung diseases. We have found that specific molecules called ICAM-1 and ICAM-2 on the lung cells are required for leukocytes to move into different parts of the lung and we have shown that other proteins called Slits can alter the migration of the leukocytes. We have also shown that ICAM-1 and -2 are present at different levels between the airways and in the alveoli. In addition there is a difference in levels of Slits between the airways and the alveoli. We suggest that differential expression and regulation of key adhesion molecules such as ICAM-1 and ICAM-2, together with Slits, act to localise leukocytes to the airways instead of the alveoli. We propose that such localisation promotes resolution of inflammation and our project will investigate this further. Our ultimate aim is to develop novel agents to aid recovery of patients with lung inflammation.