Sixty years of surfactant
research
In November 1989, a floating congress on the River Rhine was organized by Drs. B. Lachmann, L. M. G. van Golde, and J. Siebelink. The purpose of this congress was to celebrate the “60 years of surfactant research” by bringing scientists together to share their recent research findings on pulmonary surfactant. Historically, Kurt von Neergaard was the first to suggest that surface tension played an important role in lung expansion. His work was published in 1929 in a paper entitled “New notions on a fundamental principle of respiratory mechanics: the retractile force of the lung, dependent on the surface tension in the alveoli.” (translated from German). No further work was performed on this topic until the 1950s when Clements showed that lungs contain a surface tension-lowering substance and shortly thereafter Avery and Mead made the observation that lungs of infants with respiratory distress syndrome have impaired ability to lower surface tension. The topics that were discussed in the course of this congress included morphological analysis of the type II cell and of surfactant, structure and function relationships of the surfactant proteins, biophysical properties of surfactant, and surfactant replacement therapy. TYPE
II
CELL
AND
SURFACTANT
STRUCTURE
Preparation of the fetal lung for air breathing requires both qualitative and quantitative changes in the ability of the type II alveolar epithelial cell to synthesize and secrete a lipoprotein complex called pulmonary surfactant. This complex consists of lipids, primarily phospholipids and proteins. The three surfactant-specific proteins discussed here are SP-A, SP-B, and SP-C. Ontogenie changes in the type II cell and expression of type II cell-specific proteins were discussed by a number of investigators. The type II cell undergoes a number of changes during development. In early stages of rat lung development, lamellar bodies, surfactant-containing structures, are polarized at the basal cell surface, whereas at 2 wk after birth this polarization is lost. Foot processes making contact with interstitial fibroblasts are maximal at the day of birth, perhaps providing the contact needed for the epithelial-mesenchymal interactions that are thought to occur around this time. The shape of mitochondria also changes during development moving from single spherical organelles in fetal type II cell to complex branched structures in adult. Differences in the localization of the surfactant proteins SP-A and SP-B are also observed in human fetal type II cell as determined by immunohistochemistry. SP-A is found mostly in alveolar spaces, whereas SP-B is mostly within cells. In rats there L238
1040-0605/90 $1.50 Copyright
0
are differences in the expression of SP-A and SP-B in the perinatal period. Quantitative and qualitative changes in the alveolar surfactant pool also appear to exist during postnatal lung development, perhaps reflecting alterations in surfactant metabolism and/or regulation. Many of the ontogenic changes have been shown to be regulated by several classes of hormones, particularly glucocorticoids. These hormones, in addition to acting directly on the type II cell, also appear to play an important role in the pulmonary epithelial-mesenchymal interactions, which, in turn, can affect the process of lung maturation. Characterization of one of the morphological forms of surfactant, tubular myelin, was discussed in a number of papers. Pulmonary surfactant is found in a number of morphological forms including lamellar bodies, tubular meylin (TM), vesicular structures, parallel membrane structures, and others. Data were presented to indicate that the in vitro formation of TM requires dipalmitoyl phosphatidylcholine (DPPC), phosphatidylglycerol (PG), Ca 2+, and the surfactant proteins A and B. Parallel membrane structures were also seen under these conditions. Absence of SP-B results in lack of TM, with parallel membranes and vesicular structures still being present. A temperature of 45°C which is above the solidto-fluid transition of DPPC, results in disintegration of TM. An electron-microscopic analysis localized SP-A predominantly at the corners of TM network with its concentration being higher in this structure compared with that in lamellar bodies. In one study, using a doublelabeling technique, SP-A and SP-B were localized in the surface monolayer, with SP-A being squeezed out during compression. A close correlation in the levels of SP-A and SP-B mRNAs (but not of SP-C) was noted in adult lung surgical specimens. This observation is of particular interest in light of the observations that both SP-A and SP-B are important for the in vitro formation of tubular myelin. The potential importance of TM or its individual protein components in normal lung function was inferred by information obtained from a diverse group of studies. Absence of TM and low levels of surfactant proteins in human tissues have been shown in a small study to correlate with respiratory distress syndrome (RDS). Furthermore, histological analysis of the lungs of near-term newborn rabbits who received monoclonal antibodies to SP-B revealed findings similar to those in neonatal hyaline membrane disease. Moveover, genomic blot analysis of DNA samples obtained from neonatal RDS patients and a random group of donors revealed Pst I restriction fragment length polymorphism (RFLP) for the human SP-B gene. This RFLP appeared with higher frequency
1990 the American
Physiological
Society
Downloaded from www.physiology.org/journal/ajplung by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 18, 2019.
MEETING
in the RDS group compared with the other group. Experiments with transgenic mice also suggested the importance of surfactant proteins for normal lung function. FUNCTIONAL
ASPECTS
OF SURFACTANT
Surface actiuity. To understand how surfactant proteins interact with the lipids and aid in the development of new, perhaps simpler and more effective surfactants, a number of approaches are being employed. Synthetic peptides matching the carboxy terminal sequence of SPB, along with the appropriate phospholipids, can exhibit in vitro biophysical and in vivo biological activities under certain conditions that are close to those observed with natural human surfactant suggesting the importance of the carboxy terminal region of this molecule. Studies where SP-B analogues were combined with DPPC and PG and tested for their ability to lower surface tension suggested that charge interactions between hydrophilic positively charged arginine residues and the polar head groups of DPPC and PG may be important in the ability of surfactants to lower surface tension. Further, charge alterations in specific polar amino acids of SP-C appear to interfere with the function of this peptide in phospholipid dispersions. A discussion with regard to surface balances currently used to measure surface tension at the air-liquid interface and therefore evaluate the various surfactant preparations was also presented. It appears that each of the available surface balances gives slightly different information. These balances include the “traditional” Langmuir-Wilhelmy type as well as the bubble balances, where shape analysis and pressure measurements are used to determine surface tension. Potential ways of studying the monolayer using fluorescent dyes and Xrays were also discussed. A simple computer-based model, providing a relationship between surface forces and lung mechanics, thereby addressing properties of pressure-volume behavior of surfactant was also presented. Such a model can potentially provide a quick way for the initial evaluation of various lung surfactant preparations. The precise details as to how the various surfactant macromolecules interact with each other to lower surface tension and stabilize the alveolus are not entirely known. But evidence was presented to indicate that probably all three surfactant proteins with the appropriate phospholipid mixtures are important in reducing the surface tension, with each protein making a specific contribution to the entire process. SP-A, for example, appears to lower the Ca2+ concentration that surfactants require to lower surface tension. Phospholipid mixtures with a net negative charge and SP-A and SP-B absorb quickly at the air-liquid interface. SP-C may accelerate the speed of the surface-active monolayer formation. SP-B and SP-C (but not SP-A) were shown by freeze-fracture electron-microscopic analysis to induce fusion of unilamellar vesicles of DPPC or DPPC : PG. Other actiuities. The structural similarities of SP-A with the mannose binding protein and the complement protein, C,q, has led researchers to investigate additional functions o’f SPA. A number of papers were presented
L239
REPORT
on the potential role of SP-A in local host defense suggesting that SP-A can increase the following: 1) phagocytosis of Staphylococcus aureus bacteria by alveolar macrophages (this process appears, in addition to being time-, temperatureand concentration dependent, to be inhibited by antisera against SP-A, and to be specific to alveolar macrophages); 2) phagocytosis, by cultured monocytes, of sheep erythrocytes opsonized with either IgG or IgM and complement; and 3) phagocytosis of herpes simplex virus 1 by alveolar macrophages in a time-, temperature-, and concentration-dependent manner. Furthermore, human macrophages and monocytes were shown to bind and ingest recombinant human SP-A-coated colloidal gold particles. By electron-microscopic analysis this uptake appears to follow the coated pit-vesicle pathway with transport to secondary lysosomes. The interaction of SP-A with the cells may involve a mannose-dependent mechanism. The possibility that surfactant may also be needed to maintain low airway resistance in the respiratory bronchioles and prevent, therefore, further complicating phenomena characteristic of neonatal RDS was also discussed. Furthermore the possibility that surfactant could minimize the damaging effects of free radicals on the lung was suggested by in vitro studies where natural surfactant appears to reduce free radicals released from activated polymorphonuclear leukocytes. Impairment of the surfactant system. Some reports were presented with regard to agents that may impair the surfactant system. Sublethal concentrations of reactive oxygen metabolites, such as hydrogen peroxide, decrease phospholipid biosynthesis by the type II cells. Catalase treatment, however, appears to protect against this impaired type II cell function. Exposing surfactant to oxidative stress can result in chemical changes of surfactant lipids that may influence its fluidity and impair its properties. A decrease in lipid fluidity was observed in surfactant derived from an oleic acid-induced ARDS model. Treatment with whole surfactant appeared to restore lipid fluidity. In that model the decreased fluidity appeared to be due to an increased content of soluble proteins. Furthermore, hydrogen peroxide or ozone can impair SP-A and result in an inhibition of SPA-induced lipid aggregation. This impairment may in turn lead to the toxic action of oxidants on the lung. The surface tension-lowering properties of surfactant appear to be sensitive to serum proteins. Various surfactant protein-based surfactants were shown to exhibit varying degrees of sensitivity to alterations of their surface tension properties by fibrinogen with SP-B-based surfactant preparations being less sensitive. SURFACTANT
REPLACEMENT
Neonatal RDS. The efficacy of surfactant replacement has been confirmed in a number of animal models of neonatal RDS and in clinical trials. This treatment has been shown to have a number of effects including (but not limited to) stabilization of alveoli, prevention of epithelial disruption during ventilation, and reduction of leakage of serum macromolecules into alveolus. Data were presented from a number of clinical trials. These
Downloaded from www.physiology.org/journal/ajplung by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 18, 2019.
L240
MEETING
studies included a multicenter European clinical study of babies with severe RDS showing that surfactant replacement therapy is influenced by several factors including sex, asphyxia, and severity of disease. The treatment in this study was a single dose of a porcine-derived surfactant that contained SP-B and SP-C. Surfactant replacement for the very low birth weight infants with RDS has also proven effective in improving the survival rate of infants without bronchopulmonary dysplasia. Use of multiple doses of surfactant therapy on more mature preterm infants with RDS resulted in diminished deterioration of lung function often seen after a good response to first dose. In addition to the naturally derived surfactants, synthetic surfactant preparations containing no surfactant proteins were proven efficacious in a number of clinical trials. Surfactant replacement by and large is effective as evidenced by its short-term effects such as improved oxygenation, medium-term effects such as improvement of lung mechanics, and long-term effects such as increase of the survival rate. In the clinical trials of surfactant therapy three types of response are observed as determined by oxygen requirements: 1) sustained response; 2) relapse; and 3) poor response. It was suggested that these three types of response may reflect three different diseases and, therefore, more effort ought to be placed on the diagnosis of RDS. A better classification of neonatal RDS appears to be needed to attempt to identify the infants that will best benefit from surfactant replacement. To aid in predicting lung maturity accurately, a combination of diagnostic tests should be used, since each test appears to complement the other to a certain extent. ARDS. The use of surfactant therapy in patients with adult respiratory distress syndrome (ARDS) was also discussed. Some evidence for derangements in pulmonary lipids in ARDS and in inflammatory lung disease was presented and a number of animal models for studying possible derangements of the surfactant system in ARDS were discussed. Surfactant replacement in some animal models for ARDS indicates that this treatment is effective when administration takes place in the early stagesof ARDS. Early treatment of ARDS can, therefore, result in a better outcome after surfactant replacement. Limited clinical trials of patients suffering from severe respiratory failure (ARDS) suggest that surfactant replacement may improve lung function in these patients. In conclusion, it is clear that surfactant therapy is here to stay. However, in the midst of excitement for the use of a new and apparently effective therapy one should not lose sight of the fact that a number of issues,, as was
REPORT
discussed in the meeting, still remain to be answered, and caution should be exercised in the use of this new therapy. For example, distinct differences appear to exist in catabolic and clearance rates of saturated phosphatidylcholine between adult and preterm or term newborn rabbits. The former exhibits high catabolic activity, whereas the latter exhibits very little catabolic activity. Such differences can affect treatment strategies because they suggest that preterm infants may not require multiple doses but that adults do, to overcome the high clearance rate. Furthermore, differences seem to exist between adult and preterm in the effects of exogenous surfactant on the recycling surfactant pathways. Recent findings have indicated that SP-A inhibits phospholipid secretion in vitro. Although it is not clear whether this occurs in vivo, it is likely that regulation of surfactant secretion will become relevant to clinical issues. Another issue to be considered in regard to surfactant therapy is whether exogenous surfactants are immunogenic and, if so, whether the presence of immune complexes will have adverse effects on the patient. We still need to acquire more information about agents that regulate the individual surfactant components and the mechanism by which they work. We need to understand how we can stimulate the endogenous production of surfactant and what kind of surfactant preparations we can use for therapy that may positively affect the endogenous surfactant production. We need to understand how and where the various surfactant components are processed from their precursor forms to their mature active forms. Gaining further information of the regulation and metabolism of surfactant will enrich our basic knowledge and will also aid in clinical decisions such as the following: Which is the optimal dose or optimal surfactant preparation ? Should we use one or multiple doses?Should we use surfactant therapy prophylactically or in rescue? How does the exogenously administered surfactant affect the metabolism of the endogenously produced surfactant? Is surfactant replacement helpful for other pulmonary disorders? And we should remember, as Dr. Obladen stated, “that our current knowledge is only a point in a continuing process of insight.” Joanna Floros Department of Pediatrics Harvard Medical School Boston, Massachusetts 02115 American Journal of Physiology: Lung Cellular and Molecular Physiology April 1990, Volume 2
Downloaded from www.physiology.org/journal/ajplung by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 18, 2019.
research
In November 1989, a floating congress on the River Rhine was organized by Drs. B. Lachmann, L. M. G. van Golde, and J. Siebelink. The purpose of this congress was to celebrate the “60 years of surfactant research” by bringing scientists together to share their recent research findings on pulmonary surfactant. Historically, Kurt von Neergaard was the first to suggest that surface tension played an important role in lung expansion. His work was published in 1929 in a paper entitled “New notions on a fundamental principle of respiratory mechanics: the retractile force of the lung, dependent on the surface tension in the alveoli.” (translated from German). No further work was performed on this topic until the 1950s when Clements showed that lungs contain a surface tension-lowering substance and shortly thereafter Avery and Mead made the observation that lungs of infants with respiratory distress syndrome have impaired ability to lower surface tension. The topics that were discussed in the course of this congress included morphological analysis of the type II cell and of surfactant, structure and function relationships of the surfactant proteins, biophysical properties of surfactant, and surfactant replacement therapy. TYPE
II
CELL
AND
SURFACTANT
STRUCTURE
Preparation of the fetal lung for air breathing requires both qualitative and quantitative changes in the ability of the type II alveolar epithelial cell to synthesize and secrete a lipoprotein complex called pulmonary surfactant. This complex consists of lipids, primarily phospholipids and proteins. The three surfactant-specific proteins discussed here are SP-A, SP-B, and SP-C. Ontogenie changes in the type II cell and expression of type II cell-specific proteins were discussed by a number of investigators. The type II cell undergoes a number of changes during development. In early stages of rat lung development, lamellar bodies, surfactant-containing structures, are polarized at the basal cell surface, whereas at 2 wk after birth this polarization is lost. Foot processes making contact with interstitial fibroblasts are maximal at the day of birth, perhaps providing the contact needed for the epithelial-mesenchymal interactions that are thought to occur around this time. The shape of mitochondria also changes during development moving from single spherical organelles in fetal type II cell to complex branched structures in adult. Differences in the localization of the surfactant proteins SP-A and SP-B are also observed in human fetal type II cell as determined by immunohistochemistry. SP-A is found mostly in alveolar spaces, whereas SP-B is mostly within cells. In rats there L238
1040-0605/90 $1.50 Copyright
0
are differences in the expression of SP-A and SP-B in the perinatal period. Quantitative and qualitative changes in the alveolar surfactant pool also appear to exist during postnatal lung development, perhaps reflecting alterations in surfactant metabolism and/or regulation. Many of the ontogenic changes have been shown to be regulated by several classes of hormones, particularly glucocorticoids. These hormones, in addition to acting directly on the type II cell, also appear to play an important role in the pulmonary epithelial-mesenchymal interactions, which, in turn, can affect the process of lung maturation. Characterization of one of the morphological forms of surfactant, tubular myelin, was discussed in a number of papers. Pulmonary surfactant is found in a number of morphological forms including lamellar bodies, tubular meylin (TM), vesicular structures, parallel membrane structures, and others. Data were presented to indicate that the in vitro formation of TM requires dipalmitoyl phosphatidylcholine (DPPC), phosphatidylglycerol (PG), Ca 2+, and the surfactant proteins A and B. Parallel membrane structures were also seen under these conditions. Absence of SP-B results in lack of TM, with parallel membranes and vesicular structures still being present. A temperature of 45°C which is above the solidto-fluid transition of DPPC, results in disintegration of TM. An electron-microscopic analysis localized SP-A predominantly at the corners of TM network with its concentration being higher in this structure compared with that in lamellar bodies. In one study, using a doublelabeling technique, SP-A and SP-B were localized in the surface monolayer, with SP-A being squeezed out during compression. A close correlation in the levels of SP-A and SP-B mRNAs (but not of SP-C) was noted in adult lung surgical specimens. This observation is of particular interest in light of the observations that both SP-A and SP-B are important for the in vitro formation of tubular myelin. The potential importance of TM or its individual protein components in normal lung function was inferred by information obtained from a diverse group of studies. Absence of TM and low levels of surfactant proteins in human tissues have been shown in a small study to correlate with respiratory distress syndrome (RDS). Furthermore, histological analysis of the lungs of near-term newborn rabbits who received monoclonal antibodies to SP-B revealed findings similar to those in neonatal hyaline membrane disease. Moveover, genomic blot analysis of DNA samples obtained from neonatal RDS patients and a random group of donors revealed Pst I restriction fragment length polymorphism (RFLP) for the human SP-B gene. This RFLP appeared with higher frequency
1990 the American
Physiological
Society
Downloaded from www.physiology.org/journal/ajplung by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 18, 2019.
MEETING
in the RDS group compared with the other group. Experiments with transgenic mice also suggested the importance of surfactant proteins for normal lung function. FUNCTIONAL
ASPECTS
OF SURFACTANT
Surface actiuity. To understand how surfactant proteins interact with the lipids and aid in the development of new, perhaps simpler and more effective surfactants, a number of approaches are being employed. Synthetic peptides matching the carboxy terminal sequence of SPB, along with the appropriate phospholipids, can exhibit in vitro biophysical and in vivo biological activities under certain conditions that are close to those observed with natural human surfactant suggesting the importance of the carboxy terminal region of this molecule. Studies where SP-B analogues were combined with DPPC and PG and tested for their ability to lower surface tension suggested that charge interactions between hydrophilic positively charged arginine residues and the polar head groups of DPPC and PG may be important in the ability of surfactants to lower surface tension. Further, charge alterations in specific polar amino acids of SP-C appear to interfere with the function of this peptide in phospholipid dispersions. A discussion with regard to surface balances currently used to measure surface tension at the air-liquid interface and therefore evaluate the various surfactant preparations was also presented. It appears that each of the available surface balances gives slightly different information. These balances include the “traditional” Langmuir-Wilhelmy type as well as the bubble balances, where shape analysis and pressure measurements are used to determine surface tension. Potential ways of studying the monolayer using fluorescent dyes and Xrays were also discussed. A simple computer-based model, providing a relationship between surface forces and lung mechanics, thereby addressing properties of pressure-volume behavior of surfactant was also presented. Such a model can potentially provide a quick way for the initial evaluation of various lung surfactant preparations. The precise details as to how the various surfactant macromolecules interact with each other to lower surface tension and stabilize the alveolus are not entirely known. But evidence was presented to indicate that probably all three surfactant proteins with the appropriate phospholipid mixtures are important in reducing the surface tension, with each protein making a specific contribution to the entire process. SP-A, for example, appears to lower the Ca2+ concentration that surfactants require to lower surface tension. Phospholipid mixtures with a net negative charge and SP-A and SP-B absorb quickly at the air-liquid interface. SP-C may accelerate the speed of the surface-active monolayer formation. SP-B and SP-C (but not SP-A) were shown by freeze-fracture electron-microscopic analysis to induce fusion of unilamellar vesicles of DPPC or DPPC : PG. Other actiuities. The structural similarities of SP-A with the mannose binding protein and the complement protein, C,q, has led researchers to investigate additional functions o’f SPA. A number of papers were presented
L239
REPORT
on the potential role of SP-A in local host defense suggesting that SP-A can increase the following: 1) phagocytosis of Staphylococcus aureus bacteria by alveolar macrophages (this process appears, in addition to being time-, temperatureand concentration dependent, to be inhibited by antisera against SP-A, and to be specific to alveolar macrophages); 2) phagocytosis, by cultured monocytes, of sheep erythrocytes opsonized with either IgG or IgM and complement; and 3) phagocytosis of herpes simplex virus 1 by alveolar macrophages in a time-, temperature-, and concentration-dependent manner. Furthermore, human macrophages and monocytes were shown to bind and ingest recombinant human SP-A-coated colloidal gold particles. By electron-microscopic analysis this uptake appears to follow the coated pit-vesicle pathway with transport to secondary lysosomes. The interaction of SP-A with the cells may involve a mannose-dependent mechanism. The possibility that surfactant may also be needed to maintain low airway resistance in the respiratory bronchioles and prevent, therefore, further complicating phenomena characteristic of neonatal RDS was also discussed. Furthermore the possibility that surfactant could minimize the damaging effects of free radicals on the lung was suggested by in vitro studies where natural surfactant appears to reduce free radicals released from activated polymorphonuclear leukocytes. Impairment of the surfactant system. Some reports were presented with regard to agents that may impair the surfactant system. Sublethal concentrations of reactive oxygen metabolites, such as hydrogen peroxide, decrease phospholipid biosynthesis by the type II cells. Catalase treatment, however, appears to protect against this impaired type II cell function. Exposing surfactant to oxidative stress can result in chemical changes of surfactant lipids that may influence its fluidity and impair its properties. A decrease in lipid fluidity was observed in surfactant derived from an oleic acid-induced ARDS model. Treatment with whole surfactant appeared to restore lipid fluidity. In that model the decreased fluidity appeared to be due to an increased content of soluble proteins. Furthermore, hydrogen peroxide or ozone can impair SP-A and result in an inhibition of SPA-induced lipid aggregation. This impairment may in turn lead to the toxic action of oxidants on the lung. The surface tension-lowering properties of surfactant appear to be sensitive to serum proteins. Various surfactant protein-based surfactants were shown to exhibit varying degrees of sensitivity to alterations of their surface tension properties by fibrinogen with SP-B-based surfactant preparations being less sensitive. SURFACTANT
REPLACEMENT
Neonatal RDS. The efficacy of surfactant replacement has been confirmed in a number of animal models of neonatal RDS and in clinical trials. This treatment has been shown to have a number of effects including (but not limited to) stabilization of alveoli, prevention of epithelial disruption during ventilation, and reduction of leakage of serum macromolecules into alveolus. Data were presented from a number of clinical trials. These
Downloaded from www.physiology.org/journal/ajplung by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 18, 2019.
L240
MEETING
studies included a multicenter European clinical study of babies with severe RDS showing that surfactant replacement therapy is influenced by several factors including sex, asphyxia, and severity of disease. The treatment in this study was a single dose of a porcine-derived surfactant that contained SP-B and SP-C. Surfactant replacement for the very low birth weight infants with RDS has also proven effective in improving the survival rate of infants without bronchopulmonary dysplasia. Use of multiple doses of surfactant therapy on more mature preterm infants with RDS resulted in diminished deterioration of lung function often seen after a good response to first dose. In addition to the naturally derived surfactants, synthetic surfactant preparations containing no surfactant proteins were proven efficacious in a number of clinical trials. Surfactant replacement by and large is effective as evidenced by its short-term effects such as improved oxygenation, medium-term effects such as improvement of lung mechanics, and long-term effects such as increase of the survival rate. In the clinical trials of surfactant therapy three types of response are observed as determined by oxygen requirements: 1) sustained response; 2) relapse; and 3) poor response. It was suggested that these three types of response may reflect three different diseases and, therefore, more effort ought to be placed on the diagnosis of RDS. A better classification of neonatal RDS appears to be needed to attempt to identify the infants that will best benefit from surfactant replacement. To aid in predicting lung maturity accurately, a combination of diagnostic tests should be used, since each test appears to complement the other to a certain extent. ARDS. The use of surfactant therapy in patients with adult respiratory distress syndrome (ARDS) was also discussed. Some evidence for derangements in pulmonary lipids in ARDS and in inflammatory lung disease was presented and a number of animal models for studying possible derangements of the surfactant system in ARDS were discussed. Surfactant replacement in some animal models for ARDS indicates that this treatment is effective when administration takes place in the early stagesof ARDS. Early treatment of ARDS can, therefore, result in a better outcome after surfactant replacement. Limited clinical trials of patients suffering from severe respiratory failure (ARDS) suggest that surfactant replacement may improve lung function in these patients. In conclusion, it is clear that surfactant therapy is here to stay. However, in the midst of excitement for the use of a new and apparently effective therapy one should not lose sight of the fact that a number of issues,, as was
REPORT
discussed in the meeting, still remain to be answered, and caution should be exercised in the use of this new therapy. For example, distinct differences appear to exist in catabolic and clearance rates of saturated phosphatidylcholine between adult and preterm or term newborn rabbits. The former exhibits high catabolic activity, whereas the latter exhibits very little catabolic activity. Such differences can affect treatment strategies because they suggest that preterm infants may not require multiple doses but that adults do, to overcome the high clearance rate. Furthermore, differences seem to exist between adult and preterm in the effects of exogenous surfactant on the recycling surfactant pathways. Recent findings have indicated that SP-A inhibits phospholipid secretion in vitro. Although it is not clear whether this occurs in vivo, it is likely that regulation of surfactant secretion will become relevant to clinical issues. Another issue to be considered in regard to surfactant therapy is whether exogenous surfactants are immunogenic and, if so, whether the presence of immune complexes will have adverse effects on the patient. We still need to acquire more information about agents that regulate the individual surfactant components and the mechanism by which they work. We need to understand how we can stimulate the endogenous production of surfactant and what kind of surfactant preparations we can use for therapy that may positively affect the endogenous surfactant production. We need to understand how and where the various surfactant components are processed from their precursor forms to their mature active forms. Gaining further information of the regulation and metabolism of surfactant will enrich our basic knowledge and will also aid in clinical decisions such as the following: Which is the optimal dose or optimal surfactant preparation ? Should we use one or multiple doses?Should we use surfactant therapy prophylactically or in rescue? How does the exogenously administered surfactant affect the metabolism of the endogenously produced surfactant? Is surfactant replacement helpful for other pulmonary disorders? And we should remember, as Dr. Obladen stated, “that our current knowledge is only a point in a continuing process of insight.” Joanna Floros Department of Pediatrics Harvard Medical School Boston, Massachusetts 02115 American Journal of Physiology: Lung Cellular and Molecular Physiology April 1990, Volume 2
Downloaded from www.physiology.org/journal/ajplung by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 18, 2019.
