Distribution of circulation rates within a single tissue type.

An analysis is undertaken to determine the continuous distribution of circulation rates which would be necessary for a single tissue type to display a simple exponential response for the exchange of a solute with blood. It is shown that there can be no more than one real solution. This indicates that heterogeneous circulation cannot be invoked to explain anomalies to the popular assumption that blood perfusion is the process limiting the rate of blood-tissue exchange.

Chemical facilitation of thermal conduction in physiological systems.

Experimental evidence supports the concept that solutes capable of reversible chemical reaction can passively facilitate thermnal conduction within their solutions. Myoglobin and bicarbonate are suggested as energy carriers in muscle, having the combined capacity for conveying all waste metabolic heat produced under normal physiological conditions. The concept is extended to convective heat transfer in vivo; this implicates hemoglobin.

Role of surface-active phospholipids in gastric cytoprotection.

Intragastric administration of a liposomal surfactant suspension markedly reduced acid-induced gastric ulcerogenesis and bleeding in rats. The concentration of surface-active molecules intrinsically present in the gastric mucosa was increased two to six times by administration of 16,16-dimethyl prostaglandin E2. Thus, local accumulation of surface-active phospholipids may be an integral component of the cytoprotective mechanism activated by prostaglandin treatment.

'Free' surfactant in gastric aspirates and bronchoalveolar lavage in children with and without reflux oesophagitis.

AIM: Dipalmitoylphosphatidycholine (DPPC) is the characteristic and main constituent of surfactant. Adsorption of surfactant to epithelial surfaces may be important in the masking of receptors. The aims of the study were to (i) compare the quantity of free DPPC in the airways and gastric aspirates of children with gastroesophageal reflux disease (GORD) to those without and (ii) describe the association between free DPPC levels with airway cellular profile and capsaicin cough sensitivity. METHODS: Children aged <14 years were defined as 'coughers' if a history of cough in association with their GORD symptoms was elicited before gastric aspirates and nonbronchoscopic bronchoalveolar lavage (BAL) were obtained during elective flexible upper gastrointestinal endoscopy. GORD was defined as histological presence of reflux oesophagitis. Spirometry and capsaicin cough-sensitivity test was carried out in children aged >6 years before the endoscopy. RESULTS: Median age of the 68 children was 9 years (interquartile range (IQR) 7.2). Median DPPC level in BAL of children with cough (72.7 microg/mL) was similar to noncoughers (88.5). There was also no significant difference in DPPC levels in both BAL and gastric aspirates of children classified according to presence of GORD. There was no correlation between DPPC levels and cellular counts or capsaicin cough-sensitivity outcome measures. CONCLUSION: We conclude that free DPPC levels in the airways and gastric aspirate is not influenced by presence of cough or GORD defined by histological presence of reflux oesophagitis. Whether quantification of adsorbed surfactant differs in these groups remain unknown. Free DPPC is unlikely to have a role in masking of airway receptors.

A common physical basis for the gastric mucosal barrier and the action of sucralfate.

A novel explanation for the action of sucralfate in gastric ulcers has been proposed based on a new theory for gastric mucosal protection derived, in effect, from the very common industrial practice of adsorbing surfactants to surfaces needing protection against acid. Standard physical tests have been employed to show that sucralfate is highly surface-active at both liquid and solid interfaces, with the capability to be adsorbed--but not as active as the indigenous surface-active phospholipid (SAPL). This finding can explain the ability of sucralfate to "bind" to an ulcer site. Unlike SAPL or surfactants in general, adsorbed sucralfate does not render hydrophilic surfaces hydrophobic, suggesting a dual role in substituting for both SAPL and the mucus needed to stabilize it. Electron microscopy, using a novel fixation procedure specifically designed to allow for the known properties of any gastric mucosal barrier, revealed essentially the same oligolamellar lining of SAPL as previously reported in rats. Prolonged (16-day) exposure to sucralfate did not appear to change the situation, whereas there were as many, if not more, lamellar bodies (freshly secreted SAPL) adjacent to the stomach wall. Mucus-free oxyntic ducts showed the same oligolamellar lining as controls. An interesting new finding was the presence of oligolamellar SAPL as the intergranular matrix of gastric mucus--as though preparing to protect the next layer in anticipation of the surface mucin granules being eroded.

Rapidly alternating curvature ("oil canning") as a mechanism preventing alveolar edema.

This study has been designed to investigate the concept that the passage of red blood cells (clearly seen "bulging" into the air space in all scanning electron micrographs of the alveolar surface) can produce a net force tending to return any excess fluid to the interstitium. Measurements of surface tension over the time frame and probable surface area excursion incurred by a passing red blood cell show an appreciably higher value corresponding to the expanding surface, which is convex with respect to air, than when it is compressing and concave. The mean difference in surface tension of about 16 dyn/cm (mN/m) translates into a net driving force of approximately 6 mmHg induced by this rapidly alternating microcurvature reflecting the highly dynamic state of the living alveolar wall. The significance of the microcurvature of the alveolar surface is emphasized in relation to surfactant function.

Graphite-like lubrication of mesothelium by oligolamellar pleural surfactant.

Six studies have been completed to reevaluate pleural surfactant as a possible boundary lubricant in mesothelial sliding. It is capable of remarkable antiwear action, giving a mean scar diameter on a standard "four-ball test" comparable to the best commercially available lubricants and reducing friction to values anticipated from lamellated solid lubricants such as graphite. Pleural surfaces displayed appreciable hydrophobicity, which was almost eliminated by rinsing with a lipid solvent from which phospholipid was recovered and quantified. These quantities indicated that equivalent of 7.3 adsorbed monolayers of surface-active phospholipid, which was in general agreement with the number of layers of a graphite-like surface coating visualized by electron microscopy by use of a novel fixation procedure that avoids conventional aldehydes known to destroy hydrophobic surfaces. Graphite-like (dry) lubrication by adsorbed surface-active phospholipid is discussed as an excellent lubrication system available wherever the distribution of fluid allows the pleura to make contact.

An alternative view of the role(s) of surfactant and the alveolar model.

Currently, the study of surfactant proteins is much in vogue, but, in the early days, the physics underlying surfactant function was treated somewhat superficially, leaving assumptions that have become culturally embedded, such as the "bubble" model of the alveolus. This review selectively reexamines these assumptions, comparing each combination of alveolar model and role of surfactant for compatibility with the major features of pulmonary mechanics and alveolar stability, morphology, and fluid balance.

Transpulmonary passage of venous air emboli.

Twenty-seven paralyzed anesthetized dogs were embolized with venous air to determine the effectiveness of the pulmonary vasculature for bubble filtration or trapping. Air doses ranged from 0.05 to 0.40 ml X kg-1 X min-1 in 0.05-ml increments with ultrasonic Doppler monitors placed over arterial vessels to detect any microbubbles that crossed the lungs. Pulmonary vascular filtration of the venous air infusions was complete for the lower air doses ranging from 0.05 to 0.30 ml X kg-1 X min-1. When the air doses were increased to 0.35 ml X kg-1 X min-1, the filtration threshold was exceeded with arterial spillover of bubbles occurring in 50% of the animals and reaching 71% for 0.40 ml X kg-1 X min-1. Significant elevations were observed in pulmonary arterial pressure and pulmonary vascular resistance. Systemic blood pressure and cardiac output decreased, whereas left ventricular end-diastolic pressure remained unchanged. The results indicate that the filtration of venous bubbles by the pulmonary vasculature was complete when the air infusion rates were kept below a threshold value of 0.30 ml X kg-1 X min-1.

Release and lubricating properties of amniotic surfactants and the very hydrophobic surfaces of the amnion, chorion, and their interface.

Surface hydrophobicity of 17 fresh human chorioamniotic membranes was measured as the contact angle (theta) subtended when a drop of saline is placed upon any non-wettable surface. The contact angle averaged 75.5 +/- 4.2 degrees and 76.8 +/- 5.6 degrees on the epithelial surfaces of the amnion and chorion, respectively. The interface proved to be particularly hydrophobic, averaging 108.2 +/- 8.7 degrees on the amnionic side and 121.7 +/- 4.2 degrees on the chorionic side, especially when compared with 108 degrees for Teflon. High surface hydrophobicity implies good boundary (solid-to-solid) lubrication, good release from neighboring tissues, and water repellency, which is a possible factor enabling the chorioamniotic membrane to retain amniotic fluid. Good release (68 to 71%) and boundary lubrication (coefficient of kinetic friction = 0.24 +/- 0.072) were obtained from oriented monolayers of the phospholipid extracted from samples of human amniotic fluid obtained from term patients by amniocentesis. These results support the concept that the amnionic and chorionic membrane surfaces exhibit good release and boundary lubrication probably imparted by adsorbed surfactant.

Surfactants identified in lung lymph and their ability to act as abhesives.

Phospholipid has been extracted from pulmonary lymph collected from 10 dogs. Thin-layer chromatography was used to identify phosphatidylcholine (PC) 55.6 +/- 2.9%, sphingomyelin 21.3 +/- 1.7%, phosphatidylethanolamine 11.2 +/- 4.9%, and lysophosphatidylcholine 5.9 +/- 0.8%. All extracts proved highly surface active, reducing the surface tension of saline to 27.7 +/- 0.7 dyn/cm upon 80% film compression and increasing the maximum contact angle on glass (theta) from 7 +/- 1 to 47.4 +/- 1.4 degrees. The hydrophobic properties induced on glass were further demonstrated by the ability to cause saline to withdraw and expose a dry surface. A standard adhesion test was used to measure the "tack" produced by the major proteins in lymph. However, when the surface energy of the hydrophilic glass surfaces was reduced by a monolayer of lymph phospholipid extract or an equivalent mixture of synthetic surfactants, the adhesive force was reduced by 79 +/- 4% for albumin and 55 +/- 4% for globulin. As a 0.1% liposomal suspension, PC gave 55% release with albumin. Reversible bonding of the lumen of lymph vessels by the "tacky" proteins present is discussed as a possible factor contributing to the large changes in flow resistance known to occur in the pulmonary lymphatic system.

Arrest of metastatic cells: agents promoting and inhibiting instant non-specific adhesion by fibronectin.

A standard mechanical test was used to quantify instant non-specific adhesion provided in vitro by fibronectin and to demonstrate how this adhesive found on circulating tumour cells can be decreased in potency by 65% when the adherents are coated with dipalmitoyl phosphatidylcholine (DPPC). By comparison, the binding force is increased 97% by addition of sialic acid found on the more potent metastatic cells. The very tacky adhesive resulting from this mixture now fails to be inhibited by DPPC but not by phosphatidylethanolamine found in blood (1). These factors could determine whether a metastatic cell will arrest upon initial contact with a potential host tissue.

An 'engine' phenomenon displayed by monolayers of a pulmonary surfactant cycled to steady state.

Monolayers of dipalmitoyl phosphatidylcholine--the predominant lung surfactant--have been studied at the surface of buffered Ringer's solution at 37 degrees C using the Langmuir trough with surface tension measured by both the Wilhelmy and du Noüy methods. When the surface was loaded with surfactant in excess of that needed to give a condensed monolayer on compression, the films displayed the conventional loops of surface tension versus area, demonstrating large hysteresis. However, when this system was cycled several hundred times over a physiological (25%) area change, it reached a steady state in which the surface tension for compression now exceeded that for expansion at all areas. This inversion was also recorded after attaining steady state by two other approaches--low initial concentration and 'aging' for two hours--while the phenomenon was further displayed over a larger non-physiological (75%) area excursion after 90 cycles. Inversion of surface tension hysteresis under physiological conditions implies the conversion of some other form of energy into mechanical work which could aid respiration, i.e. an 'engine'. Calculations are included to show how it might make a contribution of the order of 23% to the energy needed to satisfy the work of breathing under resting conditions.

Role of surfactant in peritoneal dialysis.

Evidence is reviewed that demonstrates how the mesothelial cell in the normal peritoneum and comparable serosal cavities secretes surface-active phospholipid (SAPL) as a means of protecting itself and the membrane it forms with its neighbors. It is shown how SAPL, if adsorbed (reversibly bound) to mesothelium, can impart excellent lubricity, antiwear and release (antistick) properties, while impeding surgical adhesion formation. More-speculative benefits include acting as a deterrent to fibrosis and as a barrier to both protein leakage and pathogen invasion by spanning cell junctions. Such spanning would also "pin down" cell corners, impeding peeling as the first step in exfoliation encountered in prolonged continuous ambulatory peritoneal dialysis (CAPD). The molecular mechanism underlying each of these possible functions is adsorption. Morphological and hydrophobicity studies are discussed as validation for such an adsorbed lining and how it can be fortified by administering exogenous SAPL. Any role for SAPL in ultrafiltration is much more controversial. However, a surfactant lining can explain the very high permeability of the membrane to lipid-soluble drugs, implying that it is a barrier to water-soluble solutes. The clinical and animal evidence is conflicting but would seem to be best explained by a role for the barrier in promoting semipermeability, and hence the osmotic driving force for water transmission. Thus, adsorption of exogenous SAPL in CAPD patients with low ultrafiltration seems to restore this barrier function. The future direction for surfactant in CAPD would seem to rest with the physical chemists in producing formulations that optimize adsorption, probably involving a compromise between water solubility and surface activity of the phospholipids selected. It might even warrant using the interdialytic interval for readsorbing SAPL without the problem of dilution by a large volume of dialysate.

Surfactant barrier lining peritoneal mesothelium: lubricant and release agent.

OBJECTIVE: Five studies are described to determine whether there is an outermost lining of surface-active phospholipid (SAPL) adsorbed to the peritoneum and to quantify its ability to act as a release (antistick) agent and boundary lubricant by standard tests. METHODS: Using a hydrophobic probe (phosphin E), epifluorescence microscopy was used to demonstrate an outermost lining of oligolamellar SAPL by spectral analysis of the emitted light, a finding consistent with the appreciable hydrophobicity demonstrated on canine peritoneal mesothelium and its virtual elimination by incubation with bile salt. Good release and excellent lubricating capabilities of human peritoneal SAPL have been quantified as the release factor and coefficient of friction, respectively, by standard tests from the physical sciences. RESULTS: A well-defined outermost layer was clearly visible on peritoneal mesothelium whose color spectrum was identical to that produced by pure phosphatidylcholine ultrasonicated into its oligolamellar state. Further evidence for a SAPL lining was demonstrated by a parietal contact angle of 43 degrees (47 degrees visceral) on this surface and its virtual elimination by incubation with dilute bile salt. Human SAPL from continuous ambulatory peritoneal dialysis (CAPD) effluent proved an effective release agent, reducing adhesion by 67%, and an excellent lubricant as quantified by a coefficient of friction of 0.091 under load (1.9 kg/cm2). CONCLUSIONS: The good release and excellent lubricating properties of SAPL adsorbed to mesothelial surfaces are highly desirable in reducing wear and exfoliation of epithelial cells. In spanning epithelial cells, the same lining might also serve to render tight junctions tight and reduce macromolecular escape while compatible with many aspects of CAPD, including lipid permeability and conflicting results obtained from administering exogenous SAPL.

Possible role of adsorbed surfactant in controlling membrane permeability and function.

It is well established in the physical sciences that the adsorption of a monolayer of certain surfactants onto the surface of a synthetic membrane used for ultrafiltration can greatly modify its permeability to water and its ability to transmit small solute molecules and ions of physiological interest. In this hypothesis, it is proposed that, when indigenous surfactant is adsorbed to certain membranes in the body, it can similarly modify their permeability. Since adsorption can be a rapidly reversible process, this would provide a simple physical means of controlling the overall level of physiological activity of the membrane and, possibly, an additional means of differentiating membranes according to function. The hypothesis raises many questions concerning its applicability to the general structure of biological membranes, the nature of the surfactant, its ability to adsorb to solid surfaces and the reasons why such a coating may have been missed. There are then the questions of which membranes might benefit most and what happens if the coating is too sparse or is removed unintentionally.

Surfactant as a release agent opposing the adhesion of tumor cells in determining malignancy.

It is well established that adhesion of metastatic cells to the endothelium of the host organ is of major importance in initiating their arrest prior to invasion. However, wherever there is the potential for adhesion and subsequent disruption of normal physiological function in several other situations in vivo unrelated to cancer, the body provides a release agent in the form of surface-active phospholipids. It is proposed here that these surfactants also oppose the inherent adhesiveness of circulating tumour cells, arrest depending upon the relative potencies of glue and anti-glue. Thus, malignancy is determined not just by the "stickiness" of the metastatic emboli but by a general deficiency of surfactant or one of the host in failing to provide an adequately adsorbed layer of this release agent repelling adhesion and overall "rooting" of the seed cells. Moreover, a difference in surface activity of the release agent(s) at different sites can provide an explanation for any differential affinity observed when comparing the detachment of a cell from a primary tumour with its attachment to the host or any difference in metastatic potential of the same cells in different organs.

A mechanism for masking receptors with particular application to asthma.

This study ensconces the concept currently popular in neurophysiology that nerve terminals can be sensitized by 'unmasking' more receptors, but goes on to propose that the unknown substance masking the remainder is surface-active phospholipid. These molecules are considered to bind reversibly by adsorption to receptor surfaces just as they are known to do at a variety of tissue surfaces at which they impart 'barrier' properties very similar to those much exploited in the physical sciences. This model of nonspecific adsorption is further extended to a wide variety of receptors in lung airways including those on smooth muscle, to explain the normal control of sensitivity of reflex bronchoconstriction indicated by many physiological features. In the corollary hypothesis, asthma is attributed to a basic deficiency in surfactant causing undue unmasking of receptors exposed to the next noxious stimulus to enter the lungs. This model is shown to be compatible with the actions of a very wide variety of sensitizing agents which are physical, chemical and biological in nature; while the inflammation arising from the more biological routes can be correlated according to whether they release surfactant or disrupt it. Special attention is focused upon the diverse actions of nonsteroidal anti-inflammatory drugs versus steroids widely prescribed for asthma which promote the secretion of surfactant, as do the popular beta-agonists.

A role for oxygen-induced osmosis in hyperbaric oxygen therapy.

The principles of gas-induced osmosis, demonstrated in the 1970s, have been applied to the very large steady-state gradients of O2 arising between arterial blood and hypoxic tissue during hyperbaric oxygen (HBO) therapy to produce a fluid 'pump' in the desired direction for resolving accompanying oedema. Thus, in soft-tissue injuries, an oxygen-induced fluid pump would break the vicious cycle between ischaemia, hypoxia and oedema at the point of oedema rather than hypoxia, as hitherto assumed. This osmotic mechanism enables the successes of HBO therapy in hypoxic disorders to be reconciled with early failures in such areas as hyperbaric radiotherapy, where substitution of O2 for N2 in inspired air was clearly not reflected at the tissue level. This argument also applies to the success of HBO in treating air embolism and decompression sickness over simple compression. The oxygen pump would seem to offer a more plausible explanation for the success of HBO therapy than theories based upon O2 delivery by the circulation, especially when considering cardiovascular reflexes to elevated PaO2 and the marginal increase in blood O2 content upon switching to HBO from normobaric oxygen breathing.