Actividades para Niños

Rat alveolar epithelial cells were the first mammalian cells shown to express voltage-gated proton channels (232), but a specific function of H⫹ channels in alveolar epithelium has not been demonstrated. As in other cells, H⫹channels likely serve as a relief valve to dissipate acid under conditions of acute metabolic activity. The exquis- ite regulation of the gating of H⫹ channels by pH (see sect.VL) effectively prevents acid influx, even upon chal- lenge by apical pH 6.4 (510). This property is essential in light of the normally low pH of the alveolar subphase

FIG.23. Cartoon illustrating the proposed operation of voltage-gated proton channels during action potentials in snail neurons. See text for details. The Ca2⫹_/H⫹_{exchanger may be ATP driven (907).}

(282, 757). Low pHoat the basolateral membrane of alve-

olar epithelial monolayers elicits H⫹ influx via Na⫹/H⫹ antiport (510).

The high density of H⫹ channels in alveolar epithe- lium (Table 2) suggests a specialized purpose. One hy- pothesis is that H⫹channels might participate in the main function of the lungs, namely, elimination of CO2from the

body (235). This proposal is illustrated in Figure 24. The diffusion of CO2 across the thin barrier that separates

blood in the alveolar capillaries from air in the alveolar spaces is facilitated by the presence of CA located within the alveolar-capillary tissue barrier (284, 296, 297, 346, 388, 389, 398, 478, 551, 624a, 984, 986, 1062). Facilitated diffusion works because dissociation of CO2into HCO3⫺

and H⫹increases the concentration of diffusible species

⬃10- to 20-fold at physiological pH. This principle is also the basis for CO2transport in the blood, where, on each

passage through the systemic circulation, CO2is taken up,

converted to HCO3⫺ and H⫹, and brought to the lungs,

where CO2is reconstituted and eliminated. Inhibition of

CA II, which is present in alveolar epithelial cells, appears to reduce CO2 transport (424, 614, 972). Hereditary ab-

sence of CA II is associated with impaired CO2elimina-

tion (993) and restrictive lung disease (770), although the CO2retention in these patients might be a consequence of

the restrictive lung disease resulting from osteopetrosis, rather than the CA II deficiency per se (E. R. Swenson, personal communication). Although it is usually assumed that CO2 simply diffuses across the apical membrane,

certain epithelial cells have low CO2permeability (1054);

exit of H⫹ and HCO3⫺ would be an alternative pathway.

There are at least two potential flaws in the mechanism proposed in Figure 24. First, extrusion of H⫹ through

proton channels must be accompanied by HCO3⫺ extru-

sion, but the mechanism of the latter process can only be speculated for the present. Second, and perhaps more severe, the rate of spontaneous recombination of H⫹and HCO3⫺in the alveolar subphase (liquid lining the alveolus)

is probably too slow to account for more than a tiny fraction of the total CO2elimination (985), because this

fluid lacks CA (283, 284). It is possible that this mecha- nism operates only under extreme conditions, e.g., at high rates of CO2excretion during exercise or with lung dys-

function, such as adult respiratory distress syndrome (ARDS), in which CA may be released into the alveolar fluid with cell injury and lysis. No effect on CO2exchange

was observed when 0.5 mM ZnCl2was added to perfusate

in rabbit lungs (983), but it is not clear that sufficient Zn2⫹ reached the apical membranes of alveolar epithelial cells to inhibit H⫹ channels. A specific test of this hypothesis would be welcome but requires a specific blocker, or perhaps a tissue-specific genetic knock-out, neither of which is feasible at this time.

A voltage-gated proton conductance was recently re- ported in the cystic fibrosis JME/CF15 airway cell line, along with evidence that a similar conductance is present in human airway epithelial cultures (311). Like the alve- olar subphase fluid (282, 757), the liquid lining the apical surface of the airways is acidic. Acid secretion across the epithelium was stimulated by histamine or ATP and was inhibited by ZnCl2, but not by amiloride, ouabain, bafilo-

mycin A1, or Sch-28080 (a gastric K⫹-H⫹-ATPase inhibi- tor). Thus Fischer et al. (311) proposed that voltage-gated proton channels secrete acid into this fluid and that this histamine response might acidify the airway surface liq- uid, exacerbating asthma attacks.

FIG.24. Diagram illustrating the es- sential features of a proposed mecha- nism in which H⫹channels contribute to CO₂elimination by the lung. Briefly, CO₂ leaves the blood and crosses the endo- thelial cell layer to reach the alveolar epithelium. There is evidence that car- bonic anhydrase-catalyzed facilitated dif- fusion may contribute to CO2movement across endothelial cells (284, 624a). Car- bonic anhydrase II, present in the cyto- plasm of alveolar epithelial cells, cata- lyzes the conversion of CO2and H2O to HCO₃⫺ and H⫹(via H₂CO₃, not shown). These ions diffuse across the cell, the H⫹ bound to mobile buffer (B). H⫹leaves by permeating voltage-gated H⫹channels in the apical membrane, and HCO₃⫺leaves by Cl⫺/HCO3⫺exchange or through anion channels. The extruded HCO₃⫺ and H⫹ recombine to form CO2and H2O in the aqueous subphase, a thin layer of liquid lining the epithelial surface. CO2then en- ters the gas phase, and H₂O is reab- sorbed. See text for further details of the proposed mechanism. [From DeCoursey (235).]

F. Pulmonary Smooth Muscle: Hypoxic Pulmonary