Dissecting neutrophilic inflammation in cystic fibrosis lung disease: the role of chitinases

甲壳素是自然界中含量仅次于纤维素的第二丰富的多糖，是真菌、寄生虫和昆虫外骨骼的重要组成部分。几丁质被几丁质酶降解，几丁质酶是由低等生命形式产生的，用来抵御含有几丁质生物的感染。人们一直认为哺乳动物缺乏几丁质酶，但最近的研究表明，人类同时表达几丁质酶和几丁质酶样蛋白。我们实验室最近的研究提供了证据：(i)几丁质酶样蛋白在囊性纤维化（CF）患者的气道中积累，（ii）几丁质酶样蛋白在CF小鼠模型的肺部中上调，（iii）几丁质酶样蛋白与CF肺部疾病的肺阻塞相关，（iv）几丁质酶样蛋白受到遗传调控，(v) CF细胞释放增强的活性几丁质酶。基于这些观察，我们假设几丁质酶样蛋白和几丁质酶调节CF肺病。然而，人们对其潜在机制知之甚少。因此，我们的目标是进行以下研究：(i)研究CFTR在调节几丁质酶和几丁质酶样蛋白释放中的作用，（ii）在CF背景下解剖几丁质酶和几丁质酶样蛋白的功能，（iii）在体内治疗几丁质酶和几丁质酶样蛋白在CF肺疾病的小鼠模型中。这些研究可能为开发针对几丁质酶和几丁质酶样蛋白的特异性药物铺平道路，这可能成为CF和其他慢性炎症性疾病的一种新的治疗策略。

Chitin, the second most abundant polysaccharide in nature after cellulose, is an essential component of exoskeletons of fungi, parasites and insects. Chitin is degraded by chitinases, produced by lower life forms to defend against infections with chitin-containing organisms. It has been assumed that mammals lack chitinases, but recent studies showed that humans express both chitinases and chitinase-like proteins. Recent studies from our lab provide evidence that (i) chitinase-like proteins accumulate in the airways of cystic fibrosis (CF) patients, (ii) Chitinase-like proteins are upregulated in lungs from a CF mouse model, (iii) chitinase-like proteins correlate with pulmonary obstruction in CF lung disease, (iv) chitinase-like proteins are regulated genetically and (v) CF cells release enhanced active chitinases. Based on these observations, we hypothesize that chitinase-like proteins and chitinases modulates CF lung disease. However, the underlying mechanisms are poorly understood. Therefore, we aim to perform the following studies: (i) To investigate the role of CFTR in regulating the release of chitinases and chitinase-like proteins, (ii) to dissect the functionalities of chitinases and chitinase-like proteins in the context of CF and to (iii) therapeutically target chitinases and chitinase-like proteins in murine models of CF lung disease in vivo. These studies could pave the way for the development of specific drugs targeting chitinases and chitinase-like proteins, which could become a novel treatment strategy in CF and other chronic inflammatory diseases.