Deactivation of the pulmonary surfactant dynamics by toxic aerosols and gases.

Interactions between selected toxic aerosols and gases occurring in the air at the workplace and the pulmonary surfactant (PS) have been studied with two physicochemical techniques in vitro. The Pulsating Bubble Surfactometer (PBS) and the Langmuir-Wilhelmy Balance (LWB) have been used for measurements of dynamic interfacial properties of the PS material after its contact with several gases (sulfur dioxide, nitrogen oxides, ozone, ammonia) and liquids (sulfuric, nitric and hydrochloric acids and ammonium hydroxide), which can be brought into the alveoli with the inhaled air. Surface tension-area relationships for the interface oscillations have been analyzed using qualitative criteria of normalized hysteresis area (HA(N)) and minimum surface tension (sigma(min)). It was demonstrated that, for each analyzed compound, inactivation of the surfactant occurs, but the critical concentrations and doses are compound specific, which suggests the toxic potential of the investigated substances with respect to PS. Possible mechanisms of the interactions between the investigated substances and the surfactant components are discussed. Degradation of the PS dynamical interfacial properties (HA(N) and sigma(min)), important from the physiological viewpoint, observed in our in vitro experiments, suggests a possibility of adverse health effect in the case of a chronic inhalation of toxic gases and aerosols, even at low concentration or after a short exposure to strongly contaminated air. It results in a slowdown of the pulmonary clearance rate and increase of the lung burden for both considered cases.

Deposition and retention of ultrafine aerosol particles in the human respiratory system. Normal and pathological cases.

The particle number concentration in ambient air is dominated by nanometer-sized particles. Recent epidemiological studies report an association between the presence of nanoparticles in inhaled air at the workplace and acute morbidity and even mortality in the elderly. A theoretical model of deposition of 20 nm particles in the human alveolus was formulated. Gas flow structure and deposition rate were calculated for alveoli with different elastic properties of lung tissue. Data obtained in the paper show increased convective effects and diffusional rate of deposition of nanoparticles for alveoli with higher stiffness of the alveolar wall. The retention of deposited particles is also higher in these pathological alveoli. Results of our calculations indicate a possibility of existence of a positive loop of coupling in deposition and retention of nanoparticles in the lung with pathological changes.

Assessment of the pulmonary toxicity of inhaled gases and particles with physicochemical methods.

Physicochemical techniques used for evaluating the pulmonary surfactant (PS) quality are discussed as methods useful in assessing toxicity of inhaled gases and particles. Two standard devices, Langmuir-Wilhelmy film balance and pulsating bubble apparatus, are presented in detail, and the measured results of interaction between sulfuric acid and 2 models of PS materials are analyzed. The evident decrease in surface activity of the pulmonary surfactant after its contact with the acid at concentrations approaching 0.001 M may be considered as an indicator of the adverse effect, which can result in several health problems. The presented approach can be used as a method of assessing pulmonary toxicity of any substances present in the breathing air.

Perfluorocarbon compound aerosols for delivery to the lung as potential 19F magnetic resonance reporters of regional pulmonary pO2.

RATIONALE AND OBJECTIVES: Perfluorocarbon (PFC) aerosols present the opportunity for simultaneous analysis of lung structure and pulmonary oxygenation patterns. The authors investigated techniques to nebulize neat liquid PFCs for inhalation as a new method of PFC administration and tested the hypothesis that PFC aerosols may be developed for efficient delivery to the lung in an experimental rat model allowing the potential for sequential monitoring of pulmonary status via quantitative fluorine-19 (19F) magnetic resonance (MR) partial pressure of oxygen (pO2) imaging. METHODS: Pneumatic aerosol generators were configured to produce a neat liquid PFC perfluorotributylamine (FC-43) aerosol. Perfluorocarbon inhalation breathing protocols for the rat model included: spontaneous direct breathing from an aerosol chamber, and use of a tracheotomy tube to bypass nasal breathing. The PFC aerosol delivery into the rat lung was documented through 19F MR imaging in correlation with high-resolution anatomic proton MR images. Theoretical model calculations for PFC mass deposition were compared with experimental results. RESULTS: The pneumatic generator produced a PFC aerosol droplet within the theoretically targeted range (geometric mean particle diameter of 1.2 microns; concentration of approximately 4 x 10(7) droplets per cm3). No measurable aerosol reached the lungs during spontaneous breathing because of the efficient filtering capabilities of the turbinated nasal passages. With tracheotomy, aerosol depositions within the lung were achieved in mass quantities consistent with theoretical expectations; however, the distribution patterns were nonuniform and unpredictable. Oxygen-enhanced 19F imaging was demonstrated. CONCLUSIONS: Perfluorocarbon aerosols of controlled size distribution can be produced at sufficient concentration with pneumatic generators for distribution to the terminal pulmonary architecture and visualization using 19F MR imaging. The potential exists for in vivo oxygen-sensitive imaging in the pulmonary system and development of sophisticated experimental animal models of systemic oxygen transport as a function of pulmonary status.

Displacement of alveolar macrophages in air space of human lung.

The role of alveolar macrophages in the process of the human lung clearance is summarised. Three patterns of alveolar macrophage (AM) displacement on the surface of alveolus are distinguished depending on the loading of the surface with insoluble deposits, i.e. directional, directional with small stochastic noise and purely random. The physical analysis is presented of chemotactic movement and hydrodynamical effects on the residence time of AMs in a geometrical model of the human alveolus. The calculation of exit times from the alveolus is also presented. Calculations show that simultaneous passive and active displacement of AMs loaded with particles reduces exit time of the macrophage by 85%, compared to the case of purely directional movement. When active transport is reduced, due to AM overloading, exit time is determined by the passive transport rate. For reduced surfactant activity, the exit time of AM from the alveolus is the function of its chemotactic activity only and is inversely proportional to AM mobility. The exit time of AMs tends towards infinity when both mechanisms of clearance decay.

An improved mathematical model of hydrodynamical self-cleansing of pulmonary alveoli.

In the present paper we postulate a hydrodynamical mechanism of pulmonary alveoli cleansing and explain the role of the lung surfactant system in this phenomenon. Then a new, significantly refined mathematical model of the dynamics of the layer lining alveoli is derived and tested numerically in order to check theoretically whether the mechanism postulated can explain the phenomenon observed and to establish the influence of various physicochemical and physiological parameters on the rate of alveolar cleansing. The results obtained confirmed our hypothesis and two examples of the model verification were also shown.

Kinetics of particle retention in the human respiratory tract.

A mathematical model of retention of insoluble aerosol particles penetrating the lungs during inhalation has been described. Based on data of the streams of deposited particles and their residence times in the subsequent generations of bronchial tree the retention dynamics of particles with diameters 5, 1 and 0.01 microns in the air-spaces has been determined.

Dynamics of pulmonary surfactant system and its role in alveolar cleansing.

Qualitative descriptions of the surfactant film behaviour and the concept of hydrodynamical clearance in the alveoli are presented, and the possibilities of modelling of dynamics of this system mathematically are discussed. Using the model formulated it is shown that under dynamic conditions physiochemical surface phenomena may lead to net flow of the liquid layer (together with the dust particles) out of the alveoli. The effects of some parameters (surfactant activity and its production, viscosity of the liquid layer, size and geometry of the bronchoalveolar system, shape of respiratory curve) on the clearance rate are demonstrated. The results obtained are discussed critically.

Interactions among red cell membrane proteins.

Interactions between human red band 2.1 with spectrin and depleted inside-out vesicles were studied by fluorescence resonance energy transfer and batch microcalorimetry. The band 2.1-spectrin binding isotherm is consistent with a one to one mole ratio. The association constant of 1.4 X 10(8) M-1 corresponds to the association free energy of -11.1 kcal/mol. Under our experimental conditions, the enthalpy of interaction of band 2.1-spectrin was found to be -10.8 kcal/mol and is independent of the protein mole ratio. The calculated entropic factor (-T delta S = 0.3 kcal/mol) strongly suggests a predominantly enthalpic character of the reaction. In addition, we investigated the role of band 2.1 on the binding of band 4.1 to spectrin [Podgorski, A., & Elbaum, D. (1985) Biochemistry 24, 7871-7876] and concluded that only small, if any, alterations of binding of band 4.1 to spectrin have taken place in the presence or absence of band 2.1. This suggests thermodynamic independence of the binding sites. Although the attachment of the cytoskeletal network to the membrane takes place through, at least, two different interactions, band 2.1-band 3 and 4.1-glycophorin, the relative enthalpy values suggest that band 2.1 contributes significantly more than band 4.1 to the energy of the interaction. In addition, we observed that polymerization of actin is modulated by the cytoskeletons as judged by their effect on the rate of actin polymerization.

Properties of red cell membrane proteins: mechanism of spectrin and band 4.1 interaction.

Interactions between human red cell's band 4.1 and spectrin were studied by fluorescence resonance energy transfer and batch microcalorimetry techniques. The association constant (Ka = 8.6 X 10(7) M-1), the stoichiometry (one molecule of band 4.1 to one molecule of spectrin), the reversibility, and the enthalpy (delta H = -6 kcal/mol) were determined. A proton uptake was observed to take place as a result of the spectrin-band 4.1 complex formation. In addition to the protonation of the reaction products, the entropic contribution (-T delta S) has been observed to be responsible for approximately 50% of the binding free energy. We concluded that the environment plays a significant role in the stabilization of the complex. Since band 4.1 has been required for the maintenance of the cytoskeletal stability, small alterations of the binding energies or the degree of interaction could have a pronounced effect on the structure of the erythrocyte membrane.