Alveolar macrophages (mphi) are a crucial element of the host defense response. Nonetheless, the factors that modulate and regulate their effector functions (e.g., scavenger and secretion activities) are unclear. Our current studies show that the functions of alveolar (mphi) are selectively pH-sensitive. As such, alterations in intracellular pH (pHi) due to endogenous (e.g., increased cellular metabolism during mphi activation) or exogenous factors (e.g., pathologic changes in mphi microenvironment) can have profound effects on mphi competence. Mphi pHi is determined by the balance between processes that generate intracellular acid-base equivalents and membrane transporters that regulate the efflux of such equivalents. We have identified the major acid-base transporters in alveolar mphi: electrogenic plasmalemma V-type H+-ATPase and electroneutral exchangers (Na+/H+ and C1-/HCO3 ). These transporters link the regulation of mphi pHi, cell volume, and Em. We hypothesize that (1) in resting (unstimulated) mphi pHi and volume are both tightly regulated although with different kinetics, (2) in activated mphi pHi regulation takes precedence over volume regulation such that pHi (and pH-sensitive cell functions) are preserved at the expense of volume homeostasis, and (3) this hierarchy in housekeeping functions has important consequences for mphi activation. Previous efforts to kinetically characterize acid-base transporters have used measurements of pHi recovery from challenges induced with weak base/acid prepulses. Our studies show that this approach leads to erroneous estimates of transport kinetics, with potential errors in data interpretation. We will use tightly-coupled mathematical and experimental studies (incorporating pHi, volume, Em, and plasmalemma ion conductances/fluxes) to overcome this limitation. To test our hypotheses, we propose coupled mathematical/experimental studies to quantify the hierarchy and kinetics of pHi/volume regulation in alveolar mphi (resting or activated) and monocytes, and to determine the interaction of mphi pHi/volume regulation and oxidant production (NO, superoxide, and peroxynitrite). Our findings should provide new fundamental insights into the mechanisms that modulate alveolar mphi functions in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL051421-08
Application #
6607972
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Reynolds, Herbert Y
Project Start
1995-08-01
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
8
Fiscal Year
2002
Total Cost
$335,344
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Chakraborty, Saikat; Balakotaiah, Vemuri; Bidani, Akhil (2007) Multiscale model for pulmonary oxygen uptake and its application to quantify hypoxemia in hepatopulmonary syndrome. J Theor Biol 244:190-207
Luo, C; Clark Jr, J W; Heming, T A et al. (2006) A macrophage cell model for pH and volume regulation. J Theor Biol 238:449-63
Chakraborty, Saikat; Balakotaiah, Vemuri; Bidani, Akhil (2004) Diffusing capacity reexamined: relative roles of diffusion and chemical reaction in red cell uptake of O2, CO, CO2, and NO. J Appl Physiol 97:2284-302
Luo, Chuan; Clark Jr, John W; Heming, Thomas A et al. (2004) A simplified model for V-ATPase H+ extrusion. IEEE Trans Nanobioscience 3:257-64
Ng, Amelia W; Bidani, Akhil; Heming, Thomas A (2004) Innate host defense of the lung: effects of lung-lining fluid pH. Lung 182:297-317
Heming, Thomas A; Bidani, Akhil (2003) Intracellular pH regulation in U937 human monocytes: roles of V-ATPase and Na+/H+ exchange. Immunobiology 207:141-8
Heming, Thomas A; Bulayeva, Nataliya N; Bidani, Akhil (2003) Cell alkalosis elevates cytosolic Ca2+ in rabbit resident alveolar macrophages. Clin Sci (Lond) 105:21-8
Heming, T A; Bidani, A (2003) Effects of plasmalemmal V-ATPase activity on plasma membrane potential of resident alveolar macrophages. Lung 181:121-35
Swenson, Erik R; Deem, Steven; Kerr, Mark E et al. (2002) Inhibition of aquaporin-mediated CO2 diffusion and voltage-gated H+ channels by zinc does not alter rabbit lung CO2 and NO excretion. Clin Sci (Lond) 103:567-75
Heming, Thomas A; Bidani, Akhil (2002) Plasmalemmal H+ extruders in mammalian alveolar macrophages. Comp Biochem Physiol A Mol Integr Physiol 133:143-50

Showing the most recent 10 out of 20 publications