ALVEOLAR MACROPHAGE PHI REGULATION AND CELL FUNCTION

肺泡巨噬细胞 PHI 调节和细胞功能

• 批准号: 6389320
• 负责人: AKHIL BIDANI
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389320
• 关键词: acid base balance; acidity /alkalinity; adenosinetriphosphatase; alveolar macrophages; biophysics; cell membrane; cell morphology; enzyme activity; homeostasis; intracellular transport; laboratory rabbit; leukocyte activation /transformation; mathematical model; membrane potentials; membrane transport proteins; oxidizing agents; phagocytosis; superoxides

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.

肺泡巨噬细胞（MPHI）是宿主防御反应的关键要素。 但是，调节和调节其效应子功能的因素（例如，清道夫和分泌活动）尚不清楚。 我们目前的研究表明，肺泡（MPHI）的功能有选择地pH敏感。 因此，由于内源性（例如，MPHI激活期间的细胞代谢增加）或外源性因素（例如，MPHI微环境的病理变化）引起的细胞内pH（PHI）的改变可能对MPHI能力产生深远的影响。 MPHI PHI取决于产生细胞内酸基等效因素和调节此类等价外排的膜转运蛋白之间的平衡。 我们已经确定了肺泡MPHI中的主要酸碱转运蛋白：电基质质膜V型H+-ATPase和电自动物交换器（Na+/H+和C1-/HCO3）。 这些转运蛋白将MPHI PHI，细胞体积和EM的调节联系起来。 我们假设（1）在静止（未刺激的）mphi Phi和体积中都受到严格调节以体内稳态为代价，（3）管家功能中的层次结构对MPHI激活产生了重要的后果。 以前对酸碱转运蛋白进行动力学表征的努力已经使用了弱碱/酸/酸释放的挑战的PHI恢复的测量。 我们的研究表明，这种方法会导致转运动力学的错误估计，并在数据解释中存在潜在的错误。 我们将使用紧密耦合的数学和实验研究（纳入PHI，体积，EM和浆离电导/通量）来克服这一限制。为了检验我们的假设，我们提出了耦合的数学/实验研究，以量化肺泡MPHI（静止或激活）和单核细胞中PHI/体积调节的层次结构和动力学，并确定MPHI PHI/体积调节和氧化剂产生的相互作用（NO） ，超氧化物和过氧亚硝酸盐）。 我们的发现应为调节肺泡在健康和疾病中起作用的机制提供新的基本见解。