Evaluation of the utility of prognostic models for patients with resected hilar cholangiocarcinoma.

BACKGROUND: Several prognostic systems have been proposed to guide management strategies post-resection for patients with hilar cholangiocarcinoma. The objective of this study was to evaluate the efficacy of these conventional prognostic models, with respect to Overall Survival (OS), on patients in a modern single-centre resectional cohort. METHOD: Patients diagnosed with hilar cholangiocarcinoma, referred to a supra-regional tertiary referral centre between February 2009 and February 2016, were retrospectively analysed from a prospectively held database linked to Hospital Episode Statistics and Somerset Cancer Registry data. RESULTS: Two-hundred and one patients were assessed for suitability for surgery. Eighty-three (41%) patients considered to have potentially resectable disease underwent surgical assessment of resectability. Fifty-six (68%) patients proceeded to resection. Multivariate analysis demonstrated that pre-operative Serum CA 19-9 (p = 0.007), Radiological Arterial Involvement (p = 0.005) and Amsterdam Medical Centre (AMC) prognostic model score (p = 0.032) retained significance in association with OS. Multivariate models developed from this cohort out-performed the conventional prognostic systems for OS. CONCLUSION: The cohort-derived multivariate models demonstrated significantly improved prognostic capability compared to conventional systems in explaining OS.

Should pre-hospital resuscitative thoracotomy be reserved only for penetrating chest trauma?

PURPOSE: The indications for pre-hospital resuscitative thoracotomy (PHRT) remain undefined. The aim of this paper is to explore the variation in practice for PHRT in the UK, and review the published literature. METHODS: MEDLINE and PUBMED search engines were used to identify all relevant articles and 22 UK Air Ambulance Services were sent an electronic questionnaire to assess their PHRT practice. RESULTS: Four European publications report PHRT survival rates of 9.7, 18.3, 10.3 and 3.0% in 31, 71, 39 and 33 patients, respectively. All patients sustained penetrating chest injury. Six case reports also detail survivors of PHRT, again all had sustained penetrating thoracic injury. One Japanese paper presents 34 cases of PHRT following blunt trauma, of which 26.4% survived to the intensive therapy unit but none survived to discharge. A UK population reports a single survivor of PHRT following blunt trauma but the case details remain unpublished. Ten (45%) air ambulance services responded, each service reported different indications for PHRT. All perform PHRT for penetrating chest trauma, however, length of allowed pre-procedure down time varied, ranging from 10 to 20 min. Seventy percent perform PHRT for blunt traumatic cardiac arrest, a procedure which is likely to require aggressive concurrent circulatory support, despite this only 5/10 services carry pre-hospital blood products. CONCLUSIONS: Current indications for PHRT vary amongst different geographical locations, across the UK, and worldwide. Survivors are likely to have sustained penetrating chest injury with short down time. There is only one published survivor of PHRT following blunt trauma, despite this, PHRT is still being performed in the UK for this indication.

Prognostic molecular markers in resected extrahepatic biliary tract cancers; a systematic review and meta-analysis of immunohistochemically detected biomarkers.

UNLABELLED: Better prognostic information for resected extrahepatic cholangiocarcinoma could guide treatment strategies and potentially improve outcome. This study performed a systematic review and meta-analysis to identify prognostic biomarkers for further investigation. METHODS: Relevant literature was identified using Medline, EMBASE and Web of Science. Primary end point was overall survival assessed on univariate analysis. Log hazard ratio and variance were calculated and pooled using a random effects inverse variance approach. Hazard ratio and 95% confidence intervals were calculated. RESULTS: Thirty-seven studies, including 2371 patients, met the inclusion criteria. Subsequently nine biomarkers predictive of OS were identified (HR, 95% CI): VEGF (2.32, 1.57-3.44), COX-2 (1.94, 1.01-3.71), GLUT-1 (2.09, 1.52-2.89), Cyclin D1 (1.96, 1.02-3.76), p16 (0.68, 0.47-0.98), p27 (0.48, 0.3-0.78), E-Cadherin (0.47, 0.35-0.63), Fascin (2.19, 1.35-3.55), and Ki-67 (1.69, 1.02-2.79). CONCLUSION: Meta-analysis has identified a number of prognostic biomarkers for resected extrahepatic cholangiocarcinoma. These markers warrant further investigation as potential therapeutic targets and validation in a prospective setting.

Elevated plasma surfactant protein-B predicts development of acute respiratory distress syndrome in patients with acute respiratory failure.

Surfactant protein-B is a lung specific protein secreted into the air spaces by pulmonary epithelial type II cells that leaks into the bloodstream in increased amounts in patients with ARDS. To test whether elevated plasma levels of surfactant protein-B would predict the development of ARDS in patients with acute hypoxemic respiratory failure, plasma and lung injury scores were collected at study entry and daily thereafter for 3 d from 54 patients admitted to our intensive care unit. ARDS was defined as a new bilateral infiltrate on chest radiograph and a lung injury score > or = 2.5. Twenty patients developed ARDS, of whom seven died. Although the initial lung injury score was not predictive of ARDS, the initial plasma surfactant protein-B was predictive (area under the curve = 0.77 [0.63 to 0.90], nonparametric receiver-operating characteristic analysis). In this cohort, plasma surfactant protein-B was particularly predictive of ARDS when applied to patients suffering a direct lung insult (area under the curve = 0.87 [0.72 to 1.02]), with a sensitivity of 85% (95% CI: 55 to 98%) and specificity of 78% (40 to 97%) at a cutoff of 4,994 ng/ml.

Lung function, permeability, and surfactant composition in oleic acid-induced acute lung injury in rats.

Although acute lung injury (ALI) is associated with inflammation and surfactant dysfunction, the precise sequence of these changes remains poorly described. We used oleic acid to study the pathogenesis of ALI in spontaneously breathing anesthetized rats. We found that lung pathology can occur far more rapidly than previously appreciated. Lung neutrophils were increased approximately threefold within 5 min, and surfactant composition was dramatically altered within 15 min. Alveolar cholesterol increased by approximately 200%, and even though disaturated phospholipids increased by approximately 30% over 4 h, the disaturated phospholipid-to-total phospholipid ratio fell. Although the alveolocapillary barrier was profoundly disrupted after just 15 min, with marked elevations in lung fluid ((99m)Tc-labeled diethylenetriamine pentaacetic acid) and (125)I-labeled albumin flux, the lung rapidly began to regain its sieving properties. Despite the restoration in lung permeability, the animals remained hypoxic even though minute ventilation was increased approximately twofold and static compliance progressively deteriorated. This study highlights that ALI can set in motion a sequence of events continuing the respiratory failure irrespective of the alveolar surfactant pool size and the status of the alveolocapillary barrier.

Composition of alveolar surfactant changes with training in humans.

OBJECTIVE: We test the hypothesis that the changes we observed previously in the relative amounts of disaturated phospholipids (DSP), cholesterol (CHOL), and surfactant protein-A (SP-A) in human alveolar surfactant in response to acute exercise, and which were related to fitness, can be induced by training. METHODOLOGY: We examine the effect of 7 weeks' training on these major surfactant components, together with surfactant protein-B (SP-B), in bronchoalveolar lavage fluid harvested from 17 males, both at rest and after acute exercise. Fitness was assessed as workload/heart rate achieved during cycling for 30 min at 90% of theoretical maximal heart rate, and was increased in all subjects following training (mean increase 22.2+/-3.91%; P = 0.001). RESULTS: Training significantly increased the SP-A/DSP, SP-B/DSP, SP-A/CHOL and SP-A/SP-B ratios in whole surfactant harvested from subjects both at rest and immediately following exercise. Training also increased the SP-B/CHOL ratio at rest. Changes were particularly marked at rest in the SP-A/DSP, SP-A/CHOL, and SP-B/CHOL ratios in the tubular myelin-rich fraction, and after exercise in the SP-A/DSP, SP-A/CHOL, and SP-A/SP-B ratios in the tubular myelin-poor fraction. CONCLUSION: We conclude that training markedly alters the composition of alveolar surfactant both at rest and with exercise; the physiological significance of these changes remains to be determined.

Plasma surfactant protein-B is elevated in infants with respiratory syncytial virus-induced bronchiolitis.

Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis. However the pathophysiology of bronchiolitis is unclear. Leukocytes, especially neutrophils, may play an important role in the pathogenesis of bronchiolitis. Whereas we have previously shown that neutrophils augment epithelial leakage and detachment in RSV infection in vitro, it is unknown whether epithelial damage occurs in vivo in infants with RSV bronchiolitis. We hypothesized that respiratory epithelial damage occurs in infants with RSV bronchiolitis and that surfactant proteins leak into the circulation. The plasma concentrations of surfactant protein-A and surfactant protein-B in infants with RSV bronchiolitis were measured by ELISA. Plasma immunoreactive surfactant protein-B in infants with RSV bronchiolitis was markedly higher than that in matching controls. Our study suggests that alveolocapillary permeability is increased in infants with RSV bronchiolitis in vivo and that surfactant protein-B may be a sensitive marker for lung injury in such infants.

Immunohistochemical localization and characterization of a rat Clara cell 26-kDa protein (CC26) with similarities to glutathione peroxidase and phospholipase A2.

We have purified and partially sequenced a 26-kDa protein isolated from rat lung lavage. Two-dimensional electrophoresis and Western blotting using an antibody we have raised to this protein indicated that CC26 has 3 isoforms with pIs between 4.9 and 5.5 and is neither a component of surfactant nor present in plasma. The first 10 amino acids of the N-terminal of all 3 isoforms were identical. The first 25 amino acids of the N-terminal sequence were identical to a rat acidic calcium-independent phospholipase A2 and one amino acid different from a mouse nonselenium glutathione peroxidase. Light immunohistochemistry showed a strong reaction with the airway hypophase from the trachea down to the terminal bronchioles, but not in the alveolus. Immunohistochemistry at the electron microscopy level showed that CC26 was localized to the dense secretory bodies and endoplasmic reticulum of the Clara cell and secretory granules of tracheal nonciliated serous and goblet cells. Heavily labeled Clara cell dense secretory bodies were observed in the process of being exocytosed. Biochemical and further sequence analysis will be required to determine if this protein is either a nonselenium glutathione peroxidase or a calcium-independent phospholipase A2.

Ultrastructural and protein analysis of surfactant in the Australian lungfish Neoceratodus forsteri: evidence for conservation of composition for 300 million years.

The Australian lungfish Neoceratodus forsteri is the most primitive member of the lungfish family, with a surfactant lipid composition similar to the actinopterygiian fishes, which evolved 400 million years ago. We have analysed the proteins associated with surfactant isolated from lung lavage of this species, and used electron microscopy and immunohistochemistry to examine the surfactant structures and the subcellular localisation of these proteins. The epithelial lining of the gas-exchange region of the lungfish lung consists of one basic cell type, which has characteristics of both mammalian alveolar type I and type II cells and may be the common ancestor of both. It has long cytoplasmic plates containing microvilli, large osmiophilic bodies resembling mammalian lamellar bodies and a cytoplasm rich in metabolic organelles. Extracellular structures reminiscent of mammalian surfactant forms, but not including tubular myelin, were observed in the airspaces. Immunochemical analysis of the lungfish surfactant and lung tissue, using antibodies to human SP-A and SP-B, showed a similar staining pattern to human surfactant, indicating that SP-A- and SP-B-like proteins are present. Immunohistochemistry revealed that both SP-A and SP-B reactivity was present in the secretory cell osmiophilic bodies. In conclusion, our results suggest that, despite the great diversity in present day lung structures, a common cellular mechanism may have evolved to overcome fundamental problems associated with air-breathing.

Cyclic stretch induces both apoptosis and secretion in rat alveolar type II cells.

We examined the effects of short-term cyclic stretch on both phosphatidylcholine (PC) secretion and apoptosis in primary cultures of rat alveolar type II cells. A 22% cyclic stretch (3 cycles/min) was applied to type II cells cultured on silastic membranes using a Flexercell strain unit. This induced, after a lag period of about 1 h, a small, but significant release of [3H]PC from prelabelled cells. In addition, stretch increased nuclear condensation, the generation of oligosomal DNA fragments and the activation of caspases. Similar responses were triggered by sorbitol-induced osmotic shock, but not by the secretagogue ATP. We conclude that stretch can induce both apoptosis and PC secretion in alveolar type II cells and propose that these diverse responses occur within the lung as a consequence of normal respiratory distortion of the alveolar epithelium.

Partitioning lung and plasma proteins: circulating surfactant proteins as biomarkers of alveolocapillary permeability.

1. The alveolocapillary membrane faces an extraordinary task in partitioning the plasma and lung hypophase proteins, with a surface area approximately 50-fold that of the body and only 0.1-0.2 micron thick. 2. Lung permeability is compromised under a variety of circumstances and the delineation between physiological and pathological changes in permeability is not always clear. Although the tight junctions of the epithelium, rather than the endothelium, are regarded as the major barrier to fluid and protein flux, it is becoming apparent that the permeability of both are dynamically regulated. 3. Whereas increased permeability and the flux of plasma proteins into the alveolar compartment has dire consequences, fortuitously the flux of surfactant proteins from the airspaces into the circulation may provide a sensitive means of non-invasively monitoring the lung, with important implications for treatment modalities. 4. Surfactant proteins are unique in that they are present in the alveolar hypophase in high concentrations. They diffuse down their vast concentration gradients (approximately 1:1500-7000) into the circulation in a manner that reflects lung function and injury score. Surfactant proteins vary markedly in size (approximately 20-650 kDa) and changes in the relative amounts appear particularly diagnostic with regard to disease severity. Alveolar levels of surfactant proteins remain remarkably constant despite respiratory disease and, unlike the flux of plasma proteins into the alveolus, which may reach equilibrium in acute lung injury, the flux of surfactant proteins is unidirectional because of the concentration gradient and because they are rapidly cleared from the circulation. 5. Ultimately, the diagnostic usefulness of surfactant proteins as markers of alveolocapillary permeability will demand a sound understanding of their kinetics through the vascular compartment.

Measurement of tidal volume by using transthoracic impedance variations in rats.

The application of impedance pneumography for monitoring respiration in small animals has been limited by problems with calibration. With improved instrumentation, we describe the calibration of tidal volume in anesthetized rats. The detection of changes in voltage, reflecting the electrical impedance variations associated with respiration, was optimized by using disposable adhesive silver-silver chloride electrodes, advanced circuitry, and analog-to-digital recording instrumentation. We found a linear relationship between change in impedance and tidal volume in individual rats (R2 >/= 98%), which was strongly influenced by rat weight. Consequently, a calibration equation incorporating change in impedance and rat weight was derived to predict tidal volume. Comparison of the predicted and true tidal volumes revealed a mean R2 >/= 98%, slopes of approximately 1, intercepts of approximately 0, and bias of approximately 0.07 ml. The predicted volumes were not significantly affected by either frequency of respiration or pulmonary edema. We conclude that impedance pneumography provides a valuable tool for the noninvasive measurement of tidal volume in anesthetized rats.

Respiratory mechanics and surfactant in the acute respiratory distress syndrome.

1. Although abnormalities in pulmonary surfactant were initially implicated in the pathogenesis of the acute respiratory distress syndrome (ARDS) 30 years ago, most subsequent research has focused on mediators of the parenchymal acute lung injury (ALI) and the associated increase in alveolocapillary permeability. 2. Surfactant is essential for normal breathing and the severity of ALI correlates with surfactant dysfunction and abnormalities in surfactant composition; however, no relationship has been shown with respiratory system compliance. In neonates and most animal models, respiratory system compliance will directly reflect the elastic properties of the lung. However, the greater vertical height of the chest wall in adults, in combination with the increase in lung density due to ALI, results in dependent collapse of alveoli. Because simple, global measurement of compliance is strongly influenced by the volume of aerated lung, alternative measures of respiratory mechanics may reflect surfactant dysfunction. 3. Using a dynamic, volume-dependent model of respiratory mechanics to indirectly reflect this heterogeneous inflation, we have found direct relationships with surfactant composition in patients with ARDS. A failure of surfactant to increase surface tension in large alveoli may also explain why lung overdistension occurs at relatively low pressures. Furthermore, surfactant dysfunction will exaggerate heterogeneous lung inflation, augmenting regional overinflation, and is essential for ALI secondary to repetitive opening and closing of alveoli during tidal ventilation. 4. Ventilation-induced ALI has also been shown to result in massive increases in pro-inflammatory cytokines within the lung. Because ALI itself fails to compartmentalize cytokines, with spillover into the systemic circulation resulting in distant organ dysfunction, surfactant dysfunction may have widespread implications.

Clearance of Clara cell secretory protein 16 (CC16) and surfactant proteins A and B from blood in acute respiratory failure.

Surfactant proteins A and B (SP-A and SP-B) enter the circulation in a manner that acutely reflects changes in pulmonary function in patients with acute respiratory failure (ARF). There is a small but significant gradient in SP-A and SP-B from arterial to mixed venous (A-V) blood, and since we have detected both proteins in urine, the kidney may be a major site of their systemic clearance. Clara cell secretory protein 16 (CC16), which leaks from the respiratory tract, is known to be freely eliminated by the kidney. Lung plasma protein levels will depend on the rates of both protein entry into and clearance from plasma. In order to study the limiting variable determining these levels, we compared plasma CC16, SP-A, and SP-B in matching A-V blood samples from 37 ARF patients with indices of lung dysfunction and glomerular filtration rate (GFR) (of plasma cystatin C and creatinine). Cystatin C, CC16, SP-A, and SP-B were reduced in mixed venous plasma (all p < 0.001) and their A-V gradients were directly related to their arterial levels (all p < 0.03). Whereas CC16, SP-A, and SP-B reflected blood oxygenation (all p < 0.05), only SP-A and SP-B were related to lung injury score (LIS) (both p < 0.05). In contrast, whereas the clearances of both CC16 and cystatin C were related to that of creatinine (p < 0.02 for both), the clearances of SP-A and SP-B were not. Our study confirms that all three lung proteins are acutely cleared from the circulation of patients with ARF (half-lives < 18 min), and we conclude that whereas the plasma concentration of CC16 depends on GFR, plasma concentrations of SP-A and SP-B reflect lung function independently of this variable.

Osmotic stress induces both secretion and apoptosis in rat alveolar type II cells.

The aim of this study was to analyze the effects of osmotic shock and secretagogues such as ATP and 12-O-tetradecanoylphorbol 13-acetate (TPA) on various intracellular signaling pathways in primary cultures of alveolar type II cells and examine their potential role in regulating events such as secretion and apoptosis in these cells. Sorbitol-induced osmotic stress caused the sustained release of [3H]phosphatidylcholine ([3H]PC) from primary cultures of rat alveolar type II cells prelabeled with [3H]choline chloride. This release was not dependent on protein kinase C because downregulation of the major protein kinase C isoforms (alpha, betaII, delta, and eta) expressed in alveolar type II cells had no effect on [3H]PC secretion. Sorbitol, as well as the known secretagogues TPA and ATP, activated extracellular signal-regulated kinase. Although an inhibitor of the extracellular signal-regulated kinase cascade, PD-98059, blocked this activation, it had no effect on the release of [3H]PC. Sorbitol and ultraviolet C radiation, but not TPA or ATP, were also found to activate both p38 and stress-activated protein kinase/c-Jun NH2-terminal kinase. Furthermore, both sorbitol and ultraviolet C radiation induced apoptosis in alveolar type II cells as demonstrated by Hoechst 33258 staining of the condensed nuclei, the generation of DNA ladders, and the activation of caspases. The data indicate that multiple signaling pathways are activated by traditional secretagogues such as TPA and ATP and by cellular stresses such as osmotic shock and that these may be involved in regulating secretory and apoptotic events in alveolar type II cells.

Surfactant composition reflects lung overinflation and arterial oxygenation in patients with acute lung injury.

Pulmonary surfactant abnormalities have consistently been documented in patients with acute lung injury (ALI), however, there is little evidence directly correlating them to altered respiratory mechanics. To explore this further, surfactant composition was measured in lung aspirate fluid collected on 15 occasions from 10 patients with ALI. The composition was compared with lung aspirate fluid from 11 intubated patients prior to elective cardiac surgery (CS), and bronchoalveolar lavage fluid from 16 normal subjects. In both the ALI and cardiac groups the proportion of disaturated phospholipids (DSP) and phosphatidylcholine was reduced. Plasma levels of surfactant proteins-A and -B (SP-A and -B) were elevated, but were unrelated to alveolar surfactant levels. In the ALI group, and the ALI + CS group, DSP, normalized to the total phospholipid content, sphingomyelin (SPH), and urea, showed strong direct correlations with arterial oxygen tension/inspiratory oxygen fraction (all p < or = 0.01). In the ALI group, normalized DSP was also directly related to the elastance of the positive end-expiratory pressure-induced increase in the end-expiratory lung volume (all p < or = 0.02), and indirect correlations were found with a measure of lung overinflation (%E2; all p < or = 0.01). We conclude that surfactant composition correlates with lung function abnormalities in acute lung injury and cardiac patients, and that both groups had elevated plasma surfactant proteins-A and -B levels, consistent with a concurrent increase in alveolocapillary permeability.

Quantity and structure of surfactant proteins vary among patients with alveolar proteinosis.

Alveolar proteinosis (AP) is an idiopathic condition characterized by excess alveolar surfactant. Although the surfactant proteins (SP) are known to be aberrant, little is known of their variation between patients or their abundance relative to the lipids. We have examined surfactant composition in lavage fluid from 16 normal subjects and 13 patients with AP, one of whom was lavaged on 11 occasions over approximately 13 mo. In this patient we have examined composition on each occasion and in each sequential lavage aliquot. Composition was constant between right and left lung, but it differed markedly between patients. The cholesterol/disaturated phospholipid ratios (CHOL/DSP) were invariably elevated, on average by approximately 7-fold, whereas the SP-A/DSP and SP-B/DSP ratios were generally elevated, in some cases by as much as approximately 40- and approximately 100-fold, respectively. Although AP lavage generally contained more non-thiol-dependent SP-A aggregates and low Mr isoforms, the two-dimensional immunochemical staining patterns varied between patients and right and left lung. In the patient lavaged on multiple occasions, the SP-A/DSP and SP-B/DSP ratios progressively decreased as the patient's condition resolved. Because the SP-B/SP-A ratio was normal in all cases, we suggest that structural changes to the proteins occurred secondarily and that caution must be used in comparing functional data derived using SP-A obtained from patients with AP.

Surfactant proteins-A and -B are elevated in plasma of patients with acute respiratory failure.

Surfactant protein-A (SP-A) leaks into the circulation of patients with acute respiratory distress syndrome (ARDS) or acute cardiogenic pulmonary edema (APE) in a manner inversely related to lung function. Since surfactant protein-B (SP-B) is synthesized as a precursor considerably smaller than alveolar SP-A, we investigated whether it enters the circulation more readily. Reactivities consistent with SP-B proprotein (approximately 42 to approximately 45 kD) and the approximately 25 kD processing intermediate were detected in plasma. Plasma immunoreactive SP-B levels were significantly higher in ARDS (8,007+/-1,654 ng/ml [mean+/-SEM], n = 22) and APE (3,646+/-635 ng/ml, n = 10) patients compared with normal subjects (1,685+/-58 ng/ml, n = 33) and ventilated patients with no cardiorespiratory disease (1,829+/-184 ng/ml, n = 7). All groups had plasma SP-B/SP-A ratios approximately 6- to approximately 8-fold higher than in normal lavage or ARDS tracheal aspirate fluid, consistent with protein sieving. During admission, both plasma SP-B and the SP-B/SP-A ratio were inversely related to blood oxygenation (PaO2/FIO2) (p < 0.0001 and p < 0.025, n = 260 from 39 patients; Spearman) and static respiratory system compliance (deltaV/deltaP) (p < 0.0001 and p < 0.01, n = 168 from 25 patients). We describe in detail three patients and conclude that immunoreactive SP-B enters more readily than SP-A, is cleared acutely, and provides a better indicator of lung trauma.

Inability of histamine to regulate TNF-alpha production by human alveolar macrophages.

Tumor necrosis factor alpha (TNF-alpha), a major product of alveolar macrophages (AM), has been implicated in many pulmonary diseases. Histamine, a mediator important in pulmonary inflammation, has been demonstrated to regulate the production of TNF-alpha by monocytes. In this study, we show that human AM and monocytes differ in their responses to histamine. Whereas histamine suppressed lipopolysaccharide (LPS)-stimulated TNF-alpha production by monocytes through a cAMP-dependent mechanism, it had no effect on either cAMP levels or TNF-alpha production by AM. In contrast, both PGE2 and IL-10 suppressed LPS-stimulated TNF-alpha production by AM and monocytes. The lack of response of AM to histamine appears unique, as histamine suppressed LPS-stimulated TNF-alpha production by mononuclear cells isolated from sites of acute and chronic inflammation, as well as from noninflammatory tissues, and by macrophages differentiated in vitro. In the presence of the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine, histamine increased cAMP levels in AM. Freshly isolated monocytes and AM did not differ in PDE activity. However, PDE activity in AM, but not in monocytes, was increased 15 min after culture with histamine and may, in part, be responsible for the inability of histamine to suppress TNF-alpha production by AM. However, this increase was small and we hypothesize that additional mechanisms may contribute to the unresponsiveness of AM to histamine. We suggest that the lack of response of AM to histamine may be important in the host defense function of AM in the distal lung.

Surfactant replacement therapy in ARDS: white knight or noise in the system?

Although one would predict that surfactant replacement therapy would be effective in acute respiratory distress syndrome (ARDS), a recent large trial proved unsuccessful, possibly reflecting the nature of the surfactant used. Given the importance of the unique proteins in the action of surfactant, these would seem vital components of any exogenous surfactant. The ability to identify patients at risk of ARDS and to characterise their surfactant might allow prophylactic treatment with a nebulised, complementary, tailor-made preparation of surfactant. Advanced cases might undergo bronchoscopic focal lavage to remove plasma proteins and inflammatory mediators prior to focal instillation of surfactant to areas of greatest need. Ventilation regimens might be adjusted both to minimise trauma and to conserve endogenous surfactant.