Small Airways in Non-Cystic Fibrosis Bronchiectasis.
Small Airways in Non-Cystic Fibrosis Bronchiectasis.
复制标题
非囊性纤维化支气管扩张中的小气道。
DOI：
10.1164/rccm.202312-2275ed
复制
发表时间：
2024
影响因子：
24.7
通讯作者：
Dickey,BurtonF
中科院分区：
文献类型：
--
作者：
Dickinson,JohnD;Evans,ChristopherM;Dickey,BurtonF
Most attention in bronchiectasis has focused on large proximal airways (ie, bronchi) because they are readily observed on computed tomography imaging of the lungs and because the prominent symptom of sputum expectoration is due to the mobilization of mucus from large airways (1, 2). However, another important symptom is dyspnea, and this is due to obstruction of small distal airways (ie, bronchioles), as shown by measurement of bronchiolar resistance using a catheter, lung clearance index using a tracer gas, and air trapping by computed tomography scan (3–6). Classic studies of non–cystic fibrosis bronchiectasis (NCFB) from the 1950s found luminal mucus plugging and submucosal thickening with inflammation and increased matrix in small airways, in addition to the better-known widening of large airways (7, 8). However, the relative importance of mucus plugging versus submucosal thickening in causing airflow obstruction was not delineated, and molecular studies were not available to better define pathogenesis. Asakura and colleagues (pp. 374–389) address these gaps in knowledge in this issue of the Journal (9). Furthermore, this manuscript comes closely on the heels of two other recent manuscripts on NCFB from investigators at the University of North Carolina and collaborating institutions that together significantly advance our understanding of pathogenesis. In the first of these manuscripts, they demonstrated that mucus is hyperconcentrated in the sputum of subjects with NCFB and that mucus concentration correlates inversely with FEV1 and positively with the radiographic extent of bronchiectasis (10). This is important because of the central role that mucus hyperconcentration, due to some combination of increased mucin production and decreased ion and water transport, plays in the pathogenesis of better-studied muco-obstructive lung diseases (MOLDs), such as cystic fibrosis, chronic obstructive pulmonary disease, and asthma (11). In a second study, this group showed that airway epithelium underlying mucus plaques and plugs is hypoxic in MOLDs, including NCFB (12). In vitro studies of airway epithelial cells surprisingly showed that hypoxia in turn increases production of the major airway mucin, MUC5B, as well as expression of two subunits of the epithelial sodium channel responsible for the movement of sodium and water out of the airway lumen. Together, these changes in gene expression drive a feed-forward loop that causes further mucus hyperconcentration (Figure 1). In addition, chronic epithelial hypoxia in vitro leads to upregulation of genes involved in inflammation, which can also increase mucin expression, as well as degradative enzymes and proliferative and angiogenic factors that can cause airway remodeling.In a third study reported here, Asakura and colleagues systematically examined small airways of 11 subjects with idiopathic NCFB (9). Specimens were obtained as peripheral tissue blocks containing pleura from surgically resected lobes or autopsy lungs. Small airways were defined microscopically as being, 2 mm in diameter and free of cartilage or submucosal glands. Small airways were further divided into proximal bronchioles based on size and molecular markers (1–2 mm diameter and normally expressing MUC5B but not SCGB3A2 or SFTPB) and distal bronchioles (, 1 mm diameter and normally expressing SCGB3A2 and SFTPB but not MUC5B). In NCFB, proximal bronchioles showed upregulated MUC5B and de novo MUC5AC expression, whereas distal bronchioles showed upregulated MUC5B but no MUC5AC expression. The investigators found widespread mucus plugging of both proximal …
