HIGHLIGHTED TOPICS
Commentary

Editor, Journal of Applied Physiology

	ARTICLE

TOP ARTICLE

The first Highlighted Topics article featured in this issue of the Journal of Applied Physiology, "Mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung," by Ware and colleagues (p. 1869-1874), investigates the alveolar epithelial fluid transport capacity of human donor lungs and the response to -agonist stimulation. The authors have previously shown that intact alveolar epithelial fluid transport capacity is critical to a rapid recovery from reperfusion pulmonary edema after lung transplantation (Am J Respir Crit Care Med 159: 980, 1999). Alveolar epithelial fluid transport is also critical to the resolution of other causes of clinical pulmonary edema, including hydrostatic pulmonary edema and acute lung injury (Am J Respir Crit Care Med 163: 1376, 2001; J Appl Physiol 87: 1301, 1999). In the present study, alveolar epithelial fluid transport capacity was measured in 31 pairs of donor lungs that were rejected for transplantation. All lungs had some measurable alveolar fluid clearance, and the rate of clearance could be stimulated by the intra-alveolar administration of terbutaline, a standard ₂-adrenergic agonist. This is the first direct evidence that a -agonist can stimulate alveolar fluid clearance in the human donor lung. This finding has implications for management of transplanted lung recipients and other patients with pulmonary edema in whom the resolution of alveolar edema might be accelerated with ₂-adrenergic agonist therapy.

The second article featured in this issue, "Long-term effects of ₂-adrenergic receptor stimulation on alveolar fluid clearance in mice," by Sartori and colleagues (p. 1875-1880), also explores the effects of ₂-adrenergic agonists on alveolar fluid clearance. Administration of ₂-adrenergic agonists significantly increases the rate of alveolar fluid clearance in most species, including humans (Physiol Rev 82: 569-600, 2002). These observations suggest that ₂-adrenergic agonists might be a valuable tool if used clinically to accelerate recovery from pulmonary edema. A potential limitation of ₂-adrenergic agonist therapy for treatment of pulmonary edema, however, is the potential for -adrenoceptor (-AR) desensitization and downregulation. Thus, if alveolar epithelial cell -ARs undergo desensitization, the efficacy of ₂-adrenergic agonist therapy would diminish over time. This was recently evaluated, and a dose-dependent impairment in the ability of ₂-adrenergic agonists to increase the rate of alveolar fluid clearance after continuous isoproterenol infusion was observed in rats (Am J Physiol Lung Cell Mol Physiol 282: L666-L674, 2002). In the present study, the authors determined whether a similar phenomenon was present after a prolonged exposure to systemic ₂-adrenergic agonists and whether this functional impairment could be counterbalanced by high doses of acute intra-alveolar administration of ₂-adrenergic agonists. Toward this end, these investigators measured total lung adrenergic-induced release of cAMP and -AR density and compared both baseline and terbutaline-stimulated alveolar fluid clearance in ex vivo mice that received either saline or albuterol by continuous subcutaneous administration for 1-6 days. Continuous albuterol administration induced a significant downregulation of the -ARs in the lung and attenuated the terbutaline-induced release of cAMP. However, sustained albuterol treatment over 6 days did not diminish the acute intra-alveolar ₂-adrenergic agonist-mediated stimulation of alveolar fluid clearance. These findings represent new information that may have clinical as well as physiological relevance. First, the development of tolerance in humans to ₂-adrenergic agonists has become an important issue because tolerance has been demonstrated after only 1 wk of continuous therapy with inhaled ₂-adrenergic agonists. Whether clinically significant tolerance develops with regard to alveolar fluid clearance remains unclear. Second, and more importantly, intact epithelial function (with preserved respiratory transepithelial sodium, chloride, and fluid transport functions) is necessary for clinical improvement in patients recovering from acute lung injury (J Appl Physiol 87: 1301-1312, 1999).

The third article featured in this issue, "Limiting Na⁺ transport rate in airway epithelia from -ENaC transgenic mice: a model for pulmonary edema," by Olivier and colleagues (p. 1881-1887), explores how the rate of Na⁺ transport by airway epithelial cells and its regulation are affected in a mouse model for pulmonary edema. The highly amiloride-sensitive Na⁺ channel (ENaC) is essential for airway fluid clearance. This has been previously demonstrated in mice that are deficient in the -ENaC subunit and die at birth due to failure to clear liquid from the lung. In the present study, the authors used the -ENaC transgenic rescue (ENaC/Tg+) mouse, in which -ENaC endogenous gene expression is replaced by transgenic expression from the heterologous cytomegalovirus promoter. Contrary to the -ENaC knockout mice, the -ENaC transgenic rescue mice survive and show near normal wet-to-dry lung weight ratios. Nevertheless, these mice are prone to develop at least two forms of pulmonary edema: thiourea- and hypoxia-induced edema. To investigate the pathogenesis of this type of edema, the authors used primary cultures of tracheal cells isolated from these -ENaC transgenic rescue mice and measured transepithelial transport of Na⁺ under baseline conditions. An ~60% reduction of baseline amiloride-sensitive Na⁺ transport was observed, but its response to various regulatory factors was similar to that observed in cells from wild-type mice. Independent of the ENaC genotype, the protease inhibitor aprotinin resulted in a 50-60% reduction in transepithelial transport, and hypoxia resulted in an ~50% reduction. In all three experimental groups (wild-type, heterozygous mutant, and transgenic rescue mice), stimulation of Na⁺ transport by terbutaline under hypoxic conditions resulted in transepithelial short-circuit current values similar to those observed under control conditions. Indeed, the experimental findings match recent clinical studies in humans, which show that terbutaline treatment represents a potential therapeutic strategy to decrease pulmonary edema and improve gas exchange. In future studies, it might be of interest to determine whether ENaC/Tg+ mice are protected from developing pulmonary edema by prophylactic terbutaline inhalation. Results of the present study indicate that diminished basal Na⁺ transport per se is not a cause but possibly a predisposing factor for edema formation. Additional stresses to the system appear to be necessary; for example, stresses that occur in response to hypoxia where Na⁺ transport capacity is further reduced or in response to toxic or hydrostatic edema where fluid production is increased.

	FOOTNOTES

10.1152/japplphysiol.00791.2002