Stephen J. Lai-Fook

In conscious Wistar-Kyoto rats, we studied the uptake of radioactive tracer ¹²⁵I-albumin into the pleural space and circulation after intraperitoneal (IP) injections with 1 or 5 ml of Ringer solution (3 g/dl albumin). Postmortem, we sampled pleural liquid, peritoneal liquid, and blood plasma 2–48 h after IP injection and measured their radioactivity and protein concentration. Tracer concentration was greater in pleural liquid than in plasma ∼3 h after injection with both IP injection volumes. This behavior indicated transport of tracer through the diaphragm into the pleural space. A dynamic analysis of the tracer uptake with 5-ml IP injections showed that at least 50% of the total pleural flow was via the diaphragm. A similar estimate was derived from an analysis of total protein concentrations. Both estimates were based on restricted pleural capillary filtration and unrestricted transdiaphragmatic transport. The 5-ml IP injections did not change plasma protein concentration but increased pleural and peritoneal protein concentrations from control values by 22 and 30%, respectively. These changes were consistent with a small (∼8%) increase in capillary filtration and a small (∼20%) reduction in transdiaphragmatic flow from control values, consistent with the small (3%) decrease in hydration measured in diaphragm muscle. Thus the pleural uptake of tracer via the diaphragm with the IP injections occurred by the near-normal transport of liquid and protein.

We developed a method for measuring airway resistance (R_aw) in mice that does not require a measurement of airway flow. An analysis of R_awinduced by alveolar gas compression showed the following relationship for an animal breathing spontaneously in a closed box: R_aw= A_btV_b/[V_t(V_e+ 0.5V_t)]. Here A_btis the area under the box pressure-time curve during inspiration or expiration, V_bis box volume, V_tis tidal volume, and V_eis functional residual capacity (FRC). In anesthetized and conscious unrestrained mice, from experiments with both room temperature box air and body temperature humidified box air, the contributions of gas compression to the box pressure amplitude were 15 and 31% of those due to the temperature-humidity difference between box and alveolar gas. We corrected the measured A_btand V_tfor temperature-humidity and gas compression effects, respectively, using a sinusoidal analysis. In anesthetized mice, R_awaveraged 4.3 cmH₂O·ml⁻¹·s, fourfold greater than pulmonary resistance measured by conventional methods. In conscious mice with an assumed FRC equal to that measured in the anesthetized mice, the corrected R_awat room temperature averaged 1.9 cmH₂O·ml⁻¹·s. In both conscious mice and anesthetized mice, exposure to aerosolized methacholine with room temperature box air significantly increased R_awby around eightfold. Here we assumed that in the conscious mice both V_tand FRC remained constant. In both conscious and anesthetized mice, body temperature humidified box air reduced the methacholine-induced increase in R_awobserved at room temperature. The method using the increase in A_btwith bronchoconstriction provides a conservative estimate for the increase in R_awin conscious mice.

Elastase-induced changes in flow were used to quantify the degradation of lung interstitial elastin. Degassed rabbit lungs were inflated with silicon rubber via airways and vessels. The lungs were cut into 1-cm-thick sections. Two chambers were bonded to each section to enclose the interstitium surrounding an arterial segment. Flow of albumin solution (0–5 g/dl) between the chambers was followed by that of the albumin solution with 0.25 g/dl pancreatic elastase solution. Driving pressure was 5 cmH₂0, and mean interstitial pressure was either 0 or 10 cmH₂O. Elastase caused an increase in flow in ∼70% of the interstitial segments and a reduction in flow in the remaining segments. The elastase-induced response in flow was independent of both albumin concentration and mean interstitial pressure. Leukocyte elastase (5 units/dl) produced flow responses similar to those of 0.25 g/dl pancreatic elastase. The increased flow of leukocyte elastase was reduced by a subsequent flow with 0.25 g/dl pancreatic elastase but enhanced by a subsequent flow with a 10-fold lower concentration. A change in the order of the elastase flows reversed the concentration-dependent responses. This behavior suggests a complex interaction among the interstitial fibers after degradation by pancreatic and leukocyte elastase. Endogenous elastase-induced increases in interstitial permeability might affect blood-lymph barrier permeability, whereas elastase-induced cessation of flow might be related to the alveolar septal wall destruction observed in emphysema.

Lai-Fook, Stephen J. Pleural Mechanics and Fluid Exchange. Physiol Rev 84: 385–410, 2004; 10.1152/physrev.00026.2003.—The pleural space separating the lung and chest wall of mammals contains a small amount of liquid that lubricates the pleural surfaces during breathing. Recent studies have pointed to a conceptual understanding of the pleural space that is different from the one advocated some 30 years ago in this journal (Agostoni E. Physiol Rev 52: 57–128, 1972). The fundamental concept is that pleural surface pressure, the result of the opposing recoils of the lung and chest wall, is the major determinant of the pressure in the pleural liquid. Pleural liquid is not in hydrostatic equilibrium because the vertical gradient in pleural liquid pressure, determined by the vertical gradient in pleural surface pressure, does not equal the hydrostatic gradient. As a result, a viscous flow of pleural liquid occurs in the pleural space. Ventilatory and cardiogenic motions serve to redistribute pleural liquid and minimize contact between the pleural surfaces. Pleural liquid is a microvascular filtrate from parietal pleural capillaries in the chest wall. Homeostasis in pleural liquid volume is achieved by an adjustment of the pleural liquid thickness to the filtration rate that is matched by an outflow via lymphatic stomata.

The growth rate and albumin concentration of interstitial fluid cuffs were measured in isolated rabbit lungs inflated with albumin solution (3 g/dl) to constant airway (Paw) and vascular pressures for up to 10 h. Cuff size was measured from images of frozen lung sections, and cuff albumin concentration (C_c) was measured from the fluorescence of Evans blue labeled albumin that entered the cuffs from the alveolar space. At 5-cmH₂O Paw, cuff size peaked at 1 h and then decreased by 75% in 2 h. The decreased cuff size was consistent with an osmotic absorption into the albumin solution that filled the vascular and alveolar spaces. At 15-cmH₂O Paw, cuff size peaked at 0.25 h and then remained constant. C_c rose continuously at both pressures, but was greater at the higher pressure. The increasing C_c with a constant cuff size was modeled as diffusion through epithelial pores. Initial C_c-to-airway albumin concentration ratio was 0.1 at 5-cmH₂O Paw and increased to 0.3 at 15 cmH₂O, a behavior that indicated an increased permeability with lung inflation. Estimated epithelial reflection coefficient was 0.9 and 0.7, and equivalent epithelial pore radii were 4.5 and 6.1 nm at 5- and 15-cmH₂O Paw, respectively. The initial cuff growth occurred against an albumin colloid osmotic pressure gradient because a high interstitial resistance reduced the overall epithelial-interstitial reflection coefficient to the low value of the interstitium.