Lessons from the sweat gland on cystic fibrosis (CF) began long before modern medicine became a science. In European folklore, the curse that "a child that taste salty when kissed will soon die" (Alonso y de los Ruyzes de Fonteca J. Diez Previlegios para Mugeres Prenadas . Henares, Spain, 1606) has been taken by many as a direct reference to cystic fibrosis Busch R. Acta Univ Carol Med (Praha) 36: 13–15, 1990. The high salt concentration in sweat from patients with CF is now accepted as almost pathognomonic with this fatal genetic disease, but the earliest descriptions of cystic fibrosis as a disease entity did not mention sweat or sweat glands (Andersen DH. Am J Dis Child 56: 344–399, 1938; Andersen DH, Hodges RG. Am J Dis Child 72: 62–80, 1946). Nonetheless, defective sweating soon became an inseparable, and major, component of the constellation of symptoms that diagnose "cystic fibrosis" (Davis PB. Am J Respir Crit Care Med 173: 475–482, 2006). The sweat gland has played a foremost role in diagnosing, defining pathophysiology, debunking misconceptions, and increasing our understanding of the effects of the disease on organs, tissues, cells, and molecules. The sweat gland has taught us much. 1 Cl – concentration gives an empirical, best separation between patient and control populations. 2 Minor concentrations of glycoproteins are present in sweat (108). 3 By isotonic, it is implied that the primary fluid is similar to a plasma ultrafiltrate in composition. An exception to isotonic primary secretion is the gastric juice, but it is iso-osmotic. 4 In addition to being very large, these tests had the advantage of being performed almost exclusively in the same clinic by only a few technical personnel, which should have improved the quality of the data. 5 Cholera toxin usually requires hours to exert full effect. 6 If the paracellular shunt were permeable to either cation, the transepithelial voltage would have changed when the ion concentration was changed on either side of the epithelium. Since only Na + on the apical and only K + the basilateral affected the TEP, the tight junction cannot be permeable to either. 7 If the Cl – conductance were in the tight junction, the predominant apical membrane conductance would be Na + conductance, and Ra/Rb should have increased dramatically in response to amiloride, which it did when Cl – was removed from normal ducts and when CF ducts were used even in the presence of Cl – ,but not when Cl – was present with normal ducts. 8 ABC (ATP binding cassette) transporters are a superfamily of membrane molecules with a common amino acid motif that are known to bind and hydrolyze ATP in the transport of a wide variety of substances. 9 Again, separation of charge due to the cation Na + leading the anion Cl – across the membrane creates the electric potential (voltage), which is the driving force for passive Cl – absorption and increases as the rate of transport increases. 10 This interpretation leaves open the question of how Cl – crosses the epithelium if CFTR shuts down when ENaC activates. Possibly paracellular? (See Ref. 23.)

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