Site of Fluid Secretion in Small Airways

Abstract

The secretion and management of readily transportable airway surface liquid (ASL) along the respiratory tract is crucial for the clearance of debris and pathogens from the lungs. In proximal large airways, submucosal glands (SMGs) can produce ASL. However, in distal small airways, SMGs are absent, although the lumens of these airways are, uniquely, highly plicated. Little is known about the production and maintenance of ASL in small airways, but using electrophysiology, we recently found that native porcine small airways simultaneously secrete and absorb. How these airways can concurrently transport ASL in opposite directions is puzzling. Using high expression of the Na-K-2Cl cotransport (NKCC) 1 protein (SLC12a2) as a phenotypic marker for fluid secretory cells, immunofluorescence microscopy of porcine small airways revealed two morphologically separated sets of luminal epithelial cells. NKCC1 was abundantly expressed by most cells in the contraluminal regions of the pleats but highly expressed very infrequently by cells in the luminal folds of the epithelial plications. In larger proximal airways, the acini of SMGs expressed NKCC1 prominently, but cells expressing NKCC1 in the surface epithelium were sparse. Our findings indicate that, in the small airway, cells in the pleats of the epithelium secrete ASL, whereas, in the larger proximal airways, SMGs mainly secrete ASL. We propose a mechanism in which the locations of secretory cells in the base of pleats and of absorptive cells in luminal folds physically help maintain a constant volume of ASL in small airways.

Concurrent absorption and secretion of airway surface liquids and bicarbonate secretion in human bronchioles

“…4 and 5) indicates that neither of these agonists directly affects basolateral K ϩ conductance and therefore would not be expected to influence the observed changes in V t . These results are consistent with a model in which small airways are composed of morphologically separated secretory and absorptive cells that function independently, concurrently, and continuously to maintain an appropriate ASL volume and airway hygiene (15,50 The CFTR protein in CF is localized along the apical border of ciliated airway epithelial cells (26,58) and is best known for Cl Ϫ conductance, but it also conducts HCO 3 Ϫ (28, 34, 45) so that the morbidity and mortality from respiratory pathology in CF are consistent with a failure of HCO 3 Ϫ secretion in small airways (55,61). The data (Table 1) herein provides strong evidence that, like porcine (49), human native small airways physiologically secrete HCO 3 Ϫ constitutively and are under regulatory control as well.…”

“…Since we know of no other example of epithelial cells that can acutely reverse fluid transport directions, we asked whether the mucosal epithelia might actively absorb and secrete electrolytes simultaneously via distinct subsets of luminal epithelial cells, one that continuously adds and another that continuously removes fluid along the airway surface (15,50). To investigate these fluid transport properties, we applied a unique capillary-Ussing chamber (area Ϸ1 mm 2 ) (50) to measure transepithelial electrophysiological properties of small specimens of native, intact, freshly dissected, human small airways.…”

Gel-forming mucins form distinct morphologic structures in airways

“…These studies also have some limitations. We studied a large airway with submucosal glands, yet small airways lacking glands may also contribute to CF pathogenesis (17,39). In addition to mucins, other proteins, sugars, and lipids contribute to mucus and may influence MCT (1).…”

Cytokine-Regulation of Na+-K+-Cl− Cotransporter 1 and Cystic Fibrosis Transmembrane Conductance Regulator—Potential Role in Pulmonary Inflammation and Edema Formation

“…Regulation of transporter expression may also vary in these areas. NKCC1 has been found to be abundantly expressed in the pleats of distal airways and less in the folds (75). No change in CFTR expression was detected in different areas (75), which is not surprising assuming CFTR is involved in fluid secretion and absorption.…”

“…NKCC1 has been found to be abundantly expressed in the pleats of distal airways and less in the folds (75). No change in CFTR expression was detected in different areas (75), which is not surprising assuming CFTR is involved in fluid secretion and absorption. In lung injury, impaired alveolar fluid transport might be triggered by cytokine-mediated differential expression of ion channels including NKCC1 and CFTR that may putatively result in an increased expression and/or activation of NKCC1 and CFTR in secretory epithelia and an inhibition of channels in absorptive areas (Figure 2).…”