Role of aquaporins in lung liquid physiology

Abstract

Aquaporins (AQPs) are small, integral membrane proteins that facilitate water transport across cell membranes in response to osmotic gradients. Water transport across epithelia and endothelia in the peripheral lung and airways occurs during airway hydration, alveolar fluid transport and submucosal gland secretion. Several AQPs are expressed in the lung and airways: AQP1 in microvascular endothelia, AQP3 and AQP4 in airway epithelia, and AQP5 in type I alveolar epithelial cells, submucosal gland acini, and a subset of airway epithelial cells. Phenotype analysis of transgenic knockout mice lacking AQPs has defined their roles in the lung and airways. AQP1 and AQP5 provide the principal route for osmotically driven water transport between airspace and capillary compartments; however, alveolar fluid clearance in the neonatal and adult lung is not affected by their deletion, nor is lung fluid accumulation in experimental models of lung injury. In the airways, though AQP3 and AQP4 facilitate osmotic water transport, their deletion does not impair airway hydration, regulation of airway surface liquid, or fluid absorption. In contrast to these negative findings, AQP5 deletion in submucosal glands reduced fluid secretion by >50%. The substantially slower fluid transport in the lung compared to renal and secretory epithelia probably accounts for the lack of functional significance of AQPs in the lung and airways. Recent data outside of the lung implicating the involvement of AQPs in cell migration and proliferation suggests possible new roles for lung AQPs to be explored.

Figure 1. AQP water channel expression in lung and airways

AQPs 1, 3, 4 and 5 are expressed as indicated in epithelia and endothelia throughout the nasopharyngeal cavity, upper and lower airways, and alveoli. Information shown for mouse. See text for further explanations.

Figure 2. Mechanisms of AQP function outside of the lung

A. Reduced water permeability in glandular epithelium impairs active, near-isosmolar fluid transport by slowing osmotic water transport into the acinar lumen, producing hypertonic secretion. B. Reduced transepithelial water permeability in kidney collecting duct impairs urinary concentrating ability by preventing osmotic equilibration of luminal fluid. C. AQP-facilitated water entry into protruding lamellipodia, accounting for AQP-dependent cell migration. D. Reduced steady-state glycerol content in epidermis and stratum corneum following AQP3 deletion, accounting for reduced skin hydration in AQP3 deficiency. E. Impaired AQP7-dependent glycerol escape from adipocytes resulting in intracellular glycerol accumulation and increased triglyceride content, accounting for progressive adipocyte hypertrophy in AQP7 deficiency.

Figure 3. Water permeability and fluid transport in lungs of AQP knockout mice

A. Strategy for measurement of osmotic water permeability between the airspace/capillary barrier in isolated perfused lung as described by Carter et al. (1996). A fluorescent volume marker (F) is present in the airspace instillate, and pleural surface fluorescence is monitored in response to changes in pulmonary artery perfusate osmolality. B. Osmotically-driven water transport across the airspace/capillary barrier in lungs of wildtype mice (+/+) and knockout (−/−) mice lacking the indicated AQPs. C. Alveolar fluid clearance measured from the increased concentration of a volume marker at 15 min after instillation of isosmolar fluid at 37 °C. Where indicated, the instillate contained amiloride or mice were pre-treated with keratinocyte growth factor (KGF). Adapted from Bai et al. (1999) and Ma et al. (2000).

Figure 4. Reduced fluid secretion by airway submucosal glands in mice lacking AQP5

A. Time course of expanding fluid droplets secreted by an airway submucosal gland after pilocarpine administration. Secretion was decreased in AQP5 null mice. B. Secretion rates from individual mice shown with mean and SE. *, P < 0.01. Adapted from Song and Verkman (2001).