Immature Circulating SP-B, Bound to HDL, Represents an Early Sign of Smoke-Induced Pathophysiological Alterations.

Cigarette smoking is a major independent risk factor for cardiovascular diseases (CVD). The underlying mechanisms, however, are not clearly understood. Lungs are the primary route of exposure to smoke, with pulmonary cells and surfactant being the first structures directly exposed, resulting in the leakage of the immature proteoform of surfactant protein B (proSP-B). Herein, we evaluated whether proSP-B joined the cargo of high-density lipoprotein (HDL) proteins in healthy young subjects (n = 106) without any CVD risk factor other than smoking, and if HDL-associated proSP-B (HDL-SPB) correlated with pulmonary function parameters, systemic inflammation, and oxidative stress. At univariable analysis, HDL-SPB resulted significantly higher in smokers (2.2-fold, p < 0.001) than in non-smokers. No significant differences have been detected between smokers and non-smokers for inflammation, oxidation variables, and alveolar-capillary diffusion markers. In a multivariable model, HDL-SPB was independently associated with smoking. In conclusion, HDL-SPB is not only a precocious and sensitive index of the acute effects of smoke, but it might be also a potential causal factor in the onset of the vascular damage induced by modified HDL. These findings contribute to the emerging concept that the quality of the HDL proteome, rather than the quantity of particles, plays a central role in CVD risk protection.

Pulmonary surfactant-associated protein B regulates prostaglandin-endoperoxide synthase-2 and inflammation in chronic obstructive pulmonary disease.

NEW FINDINGS: What is the central question of this study? It is reported that polymorphism of the gene for pulmonary surfactant-associated protein B (SFTPB) is associated with chronic obstructive pulmonary disease (COPD): what are the function and mechanism of action of SFTPB in COPD? What is the main finding and its importance? Under stimulation of the risk factors of COPD, SFTPB expression is decreased, which may be involved in the formation of COPD. The progress of COPD induces an inflammatory response and reduces SFTPB expression. Levels of prostaglandin-endoperoxide synthase-2 (PTGS2) and inflammatory responses are changed by SFTPB, which indicates that SFTPB promotes the progression of COPD by PTGS2 and inflammation. ABSTRACT: Pulmonary surfactant-associated protein B (SFTPB) is a critical protein for lung homeostasis, and polymorphism of its gene is associated with chronic obstructive pulmonary disease (COPD). However, few studies have so far confirmed the functional involvement of SFTPB in COPD. Serum SFTPB and inflammatory cytokine levels were measured in 54 patients with acute exacerbation of COPD and 29 healthy controls. A549 cells were induced using 10% cigarette smoke extract (CSE) and treated with dexamethasone to investigate the effect of inflammation on SFTPB expression, and the effect of SFTPB overexpression and silencing on inflammatory cytokines was measured using real-time PCR and enzyme-linked immunosorbent assay. SFTPB expression was assessed in mouse lung tissues using immunofluorescence. Serum levels of SFTPB were significantly lower in COPD patients than in controls (P = 0.009). Conversely, levels of interleukin (IL)-6 and prostaglandin-endoperoxide synthase-2 (PTGS2) were increased in COPD patients (IL-6: P = 0.006; PTGS2: P = 0.043). After CSE treatment, SFTPB mRNA and protein levels were significantly decreased compared to controls (mRNA: P = 0.002; protein: P = 0.011), while IL-6, IL-8 and PTGS2 were elevated. Dexamethasone treatment increased SFTPB levels. Following overexpression of SFTPB in A549 cells, mRNA and protein levels of IL-6, IL-8 and PTGS2 were significantly reduced, while gene silencing induced the opposite effect. SFTPB levels were significantly reduced in the lung tissue of a mouse model of COPD compared to controls. Reduced SFTPB levels may induce PTGS2 and inflammatory responses in COPD and SFTPB could be a key protein for evaluation of COPD progression.

C-proSP-B: A Possible Biomarker for Pulmonary Diseases?

BACKGROUND: Detection of surfactant proteins A and D (SP-A and SP-D) in the serum of patients with pulmonary diseases is thought to reflect an injury of the alveolar epithelial barrier and as such serve as a biomarker for these diseases. However, the data for SP-B are limited. OBJECTIVES: The aim of this feasibility study was to assess whether immature SP-B pre-proteins might have value as a possible biomarker for pulmonary diseases. METHODS: In serum samples from patients with different chronic lung diseases (interstitial lung diseases [ILDs], chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary hypertension, inflammation, patients on ventilator support; total n = 283), C-proSP-B was measured using an electrochemiluminescence immunoassay based on mouse monoclonal anti-C-proSP-B antibodies. Levels were correlated to lung functional and clinical parameters. RESULTS: The highest C-proSP-B levels were detected in the serum of idiopathic pulmonary fibrosis (IPF) patients. In a multivariate analysis, C-proSP-B levels were able to discriminate IPF patients from patients with all other pulmonary diseases (p < 0.0001). No significant correlations were found between C-proSP-B levels and lung function, smoking history, or disease extent. CONCLUSIONS: SP-B pre-proteins might serve as a biomarker in pulmonary diseases with alveolar or interstitial damage such as ILDs, especially in IPF. Their role in the long-term monitoring of such diseases has to be clarified further.

Serum Surfactant Protein Levels in Patients Admitted to the Hospital with Acute COPD Exacerbation.

Surfactant proteins (SPs) have been studied in COPD patients as biomarkers of disease severity and as predictive factors of unfavorable outcomes. The aim of this exploratory study was to evaluate serum levels of SP-A, SP-B, SP-C, and SP-D in patients with COPD both during AECOPD and in stability and to test their possible associations with disease severity and with the development of new exacerbation events. 20 consecutive COPD patients hospitalized for AECOPD were included. Serum SP levels were measured on admission, at discharge, and on stability. SP-A levels were significantly lower both on admission and at discharge in patients with early relapse compared to those with late or no relapse (29.2 ± 9.1 vs. 43.9 ± 16.9 ng/ml, p = 0.037, and 24.3 ± 2.8 vs. 39.3 ± 14.2 ng/ml, p = 0.011, respectively). SP-B levels were found to have a trend to be higher at discharge and significantly higher on stability in patients experiencing an early relapse compared to those with late or no relapse (52.5 ± 31.6 vs. 31.4 ± 32.3 ng/ml, p = 0.052 and 64.8 ± 32.6 vs. 32.8 ± 25.6 ng/ml, p = 0.024, respectively). Finally, the ROC analysis showed that serum SP-A, SP-B, and SP-C levels at discharge, seemed to be significant predictors of early relapse. Our conclusion is that serum levels of SPs might be related to disease outcomes in COPD patients.

In vitro and in vivo comparison between poractant alfa and the new generation synthetic surfactant CHF5633.

BACKGROUND: CHF5633 is a new generation synthetic surfactant containing both SP-B and SP-C analogues developed for the treatment of respiratory distress syndrome. Here, the optimal dose and its performance in comparison to the animal-derived surfactant poractant alfa were investigated. METHODS: In vitro surfactant activity was determined by means of the Wilhelmy balance and the capillary surfactometer. The dose-finding study was performed in preterm rabbits with severe surfactant deficiency. CHF5633 doses ranging from 50 to 300 mg/kg were used. Untreated animals and animals treated with 200 mg/kg of poractant alfa were included for comparison. RESULTS: In vitro, minimum surface tension (γmin) was decreased from values above 70 to 0 mN/m by both surfactants, and they formed rapidly a film at the air-liquid interface. In vivo studies showed a clear dose-dependent improvement of lung function for CHF5633. The pulmonary effect of CHF5633 200 mg/kg dose was comparable to the pulmonary response elicited by 200 mg/kg of poractant alfa in preterm rabbits. CONCLUSION: CHF5633 is as efficient as poractant alfa in our in vitro and in vivo settings. A clear dose-dependent improvement of lung function could be observed for CHF5633, with the dose of 200 mg/kg being the most efficient one.

Genetic Polymorphisms of SP-A, SP-B, and SP-D and Risk of Respiratory Distress Syndrome in Preterm Neonates.

BACKGROUND We examined selected polymorphisms in 3 pulmonary surfactant-associated proteins (SP) for their influence on serum SP levels and risk of respiratory distress syndrome (RDS) in preterm neonates. MATERIAL AND METHODS Premature infants from a Han population were enrolled, including 100 premature infants with RDS (case group) and 120 premature infants without RDS (control group). SNP genotyping for SP-A (+186A/G and +655C/T), SP-B (-18A/C and 1580C/T), and SP-D (Met11ThrT/C and Ala160ThrG/A) used polymerase chain reaction-restriction fragment length polymorphism. Haplotypes were calculated with Shesis software and serum SP-A/B/D levels were quantified by ELISA. RESULTS Case and control groups exhibited significant differences in genotype and allele frequencies of SP-A (+186A/G, +655C/T) and SP-B (1580C/T). However, no statistically significant differences were observed in the allele and genotype frequencies of SP-B -18A/C, SP-D Met11ThrT/C, and SP-D Ala160ThrG/A. Importantly, serum SP-A and SP-B levels were reduced in RDS patients carrying SP-A (+186A/G, +655C/T) and SP-B (1580C/T) polymorphisms. AA genotype of +186A/G, SP-A level, and CC genotype of 1580C/T were independently correlated with increased RDS risk. CONCLUSIONS SP-A (+186A/G) and SP-B (1580C/T) polymorphisms are strongly associated with the risk of RDS in preterm infants. Notably, reduced serum SP-A levels were correlated with a high risk of RDS and may serve as novel biomarkers for RDS detection and monitoring.

Surfactant protein B: From biochemistry to its potential role as diagnostic and prognostic marker in heart failure.

Growing interest raised on circulating biomarkers of structural alveolar-capillary unit damage and very recent data support surfactant protein type B (SP-B) as the most promising candidate in this setting. With respect to other proteins proposed as possible markers of lung damage, SP-B has some unique qualities: it is critical for the assembly of pulmonary surfactant, making its lack incompatible with life; it has no other known site of synthesis except alveolar epithelial cells different from other surfactant proteins; and, it undergoes a proteolytic processing in a pulmonary-cell-specific manner. In the recent years circulating SP-B isoforms, mature or immature, have been demonstrated to be detectable in the circulation depending on the magnitude of the damage of alveolar capillary membrane. In the present review, we summarize the recent knowledge on SP-B regulation, function and we discuss its potential role as reliable biological marker of alveolar capillary membrane (dys)function in the context of heart failure.

Relationship between surfactant proteins B and C and obstructive sleep apnea: is serum SP-B concentration a potential biomarker of obstructive sleep apnea?

BACKGROUND: Surfactant proteins B and C are mainly synthesized, secreted by alveolar type II cells, and affected by hypoxia and mechanical stretches. We hypothesized that their serum levels might be altered by intermittent hypoxia and swing of intrathoracic pressure of obstructive sleep apnea (OSA). METHODS: Consecutive 140 middle-aged males, suspicious of OSA determined by polysomnography, were studied. Surfactant proteins B and C were determined by ELISA. RESULTS: Surfactant protein B (41.39 ± 6.01 vs 44.73 ± 7.62 ng/L, p = 0.005), not C (32.60 ± 6.00 vs 32.43 ± 6.44 ng/L, p = 0.61), significantly lowered in moderate to severe OSA subjects than in non to mild OSA subjects. Severity of OSA is inversely correlated with serum surfactant protein B. Adjusting age, body mass index, and smoking history, compared to subjects with surfactant protein B (SP-B) ≥43.35 ng/L, those with SP-B <43.35 ng/L showed significantly increased 1.528-fold risk for moderate to severe OSA (p = 0.009), whereas no association between surfactant protein C and OSA was observed. Prevalence of moderate to severe OSA in lower SP-B group is higher than that in higher SP-B group (62.7 vs 38.4 %, p = 0.003). Serial and parallel tests on Epworth sleep scale (ESS) and SP-B evaluation can be complementary and prove helpful with high specificity (94.44 %) and sensitivity (84.48 %) to detect moderate to severe OSA. CONCLUSIONS: Serum surfactant protein B, rather than C, is decreased in some individuals with moderate to severe OSA, compared to non to mild OSA subjects. Serum surfactant protein B might be a potential biomarker to diagnose OSA.

Quantification of HDL proteins, cardiac events, and mortality in patients with type 2 diabetes on hemodialysis.

BACKGROUND AND OBJECTIVES: Impairment of HDL function has been associated with cardiovascular events in patients with kidney failure. The protein composition of HDLs is altered in these patients, presumably compromising the cardioprotective effects of HDLs. This post hoc study assessed the relation of distinct HDL-bound proteins with cardiovascular outcomes in a dialysis population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The concentrations of HDL-associated serum amyloid A (SAA) and surfactant protein B (SP-B) were measured in 1152 patients with type 2 diabetes mellitus on hemodialysis participating in The German Diabetes Dialysis Study who were randomly assigned to double-blind treatment of 20 mg atorvastatin daily or matching placebo. The association of SAA(HDL) and SP-B(HDL) with cardiovascular outcomes was assessed in multivariate regression models adjusted for known clinical risk factors. RESULTS: High concentrations of SAA(HDL) were significantly and positively associated with the risk of cardiac events (hazard ratio per 1 SD higher, 1.09; 95% confidence interval, 1.01 to 1.19). High concentrations of SP-B(HDL) were significantly associated with all-cause mortality (hazard ratio per 1 SD higher, 1.10; 95% confidence interval, 1.02 to 1.19). Adjustment for HDL cholesterol did not affect these associations. CONCLUSIONS: In patients with diabetes on hemodialysis, SAA(HDL) and SP-B(HDL) were related to cardiac events and all-cause mortality, respectively, and they were independent of HDL cholesterol. These findings indicate that a remodeling of the HDL proteome was associated with a higher risk for cardiovascular events and mortality in patients with ESRD.

Surfactant-derived proteins as markers of alveolar membrane damage in heart failure.

BACKGROUND: In heart failure (HF) alveolar-capillary membrane is abnormal. Surfactant-derived proteins (SPs) and plasma receptor for advanced-glycation-end-products (RAGE) have been proposed as lung damage markers. METHODS: Eighty-nine chronic HF and 17 healthy subjects were evaluated by echocardiography, blood parameters, carbon monoxide lung diffusion (DLCO) and cardiopulmonary exercise test. We measured immature SP-B, mature SP-B, SP-A, SP-D and RAGE plasma levels. RESULTS: Immature SP-B (arbitrary units), mature SP-A (ng/ml) and SP-D (ng/ml), but not mature SP-B (ng/ml) and RAGE (pg/ml) levels, were higher in HF than in controls [immature SP-B: 15.6 (13.1, 75th-25th interquartile range) Vs. 11.1 (6.4), p<0.01; SP-A, 29.6 (20.1) Vs. 18.3 (13.5), p = 0.01; SP-D: 125 (90) Vs. 78 (58), p<0.01]. Immature SP-B, SP-A, SP-D and RAGE values were related to DLCO, peak oxygen consumption, ventilatory efficiency, and brain natriuretic peptide (BNP), whereas plasma mature SP-B was not. The DLCO Vs. immature SP-B correlation was the strongest one. At multivariate analysis, RAGE was associated to age and creatinine, SP-A to DLCO and BNP, SP-D to BNP, mature SP-B to DLCO and creatinine, and immature SP-B only but strongly to DLCO. CONCLUSIONS: Immature SP-B is the most reliable biological marker of alveolar-capillary membrane function in HF.

High postoperative serum levels of surfactant type B as novel prognostic markers for congenital heart surgery.

OBJECTIVE: Congenital heart diseases are observed in 5 to 8 of every 1000 live births. The presence of a valuable biomarker during the surgical periods may aid the clinician in a more accurate prognosis during treatment. METHODS: For this reason, surfactant protein B plasma levels may help to evaluate patients with cardiac problems diminishing the alveolocapillary membrane stability. In this study, plasma levels of this biomarker were measured in the preoperative and postoperative periods. This study was conducted to detect the differences between pulmonary hypertensive and normotensive patients. The differences before and after cardiopulmonary bypass were examined. RESULTS: The differences in cardiopulmonary bypass time, cross-clamp time , inotropic support dose, and duration of intensive care of patients with and without pulmonary hypertensive were found to be statistically significant (P<0.05). The results revealed that this pathophysiological state was related to other variables that were studied. We believe that the differences in preoperative and postoperative SPB levels could be attributed to alveolocapillary membrane damage and alveolar surfactant dysfunction. We found that this pathophysiological condition was significantly associated with postoperative parameters. CONCLUSION: The findings of the current study showed that surfactant protein B was present in the blood of patients with a congenital heart disease during the preoperative period. Long by-pass times may exert damage to the alveolocapillary membrane in patients with pulmonary hypertension and preoperative heart failure, and it is recommended to keep the option of surfactant therapy in mind during the postoperative course at the intensive care unit before preparing the patients for extubation.

High postoperative serum levels of surfactant type B as novel prognostic markers for congenital heart surgery / Níveis séricos pós-operatórios tipo surfactante B elevados como novos marcadores prognósticos para cirurgia cardíaca congênita

Objective: Congenital heart diseases are observed in 5 to 8 of every 1000 live births. The presence of a valuable biomarker during the surgical periods may aid the clinician in a more accurate prognosis during treatment. Methods: For this reason, surfactant protein B plasma levels may help to evaluate patients with cardiac problems diminishing the alveolocapillary membrane stability. In this study, plasma levels of this biomarker were measured in the preoperative and postoperative periods. This study was conducted to detect the differences between pulmonary hypertensive and normotensive patients. The differences before and after cardiopulmonary bypass were examined. Results: The differences in cardiopulmonary bypass time, cross-clamp time , inotropic support dose, and duration of intensive care of patients with and without pulmonary hypertensive were found to be statistically significant (P<0.05). The results revealed that this pathophysiological state was related to other variables that were studied. We believe that the differences in preoperative and postoperative SPB levels could be attributed to alveolocapillary membrane damage and alveolar surfactant dysfunction. We found that this pathophysiological condition was significantly associated with postoperative parameters. Conclusion: The findings of the current study showed that surfactant protein B was present in the blood of patients with a congenital heart disease during the preoperative period. Long by-pass times may exert damage to the alveolocapillary membrane in patients with pulmonary hypertension and preoperative heart failure, and it is recommended to keep the option of surfactant therapy in mind during the postoperative course at the intensive care unit before preparing the patients for extubation. .

Objetivo: As cardiopatias congênitas são observadas em 5 a 8 em cada 1.000 nascidos vivos. A presença de um biomarcador importante durante os períodos cirúrgicos pode auxiliar o clínico a um prognóstico mais preciso durante o tratamento. Métodos: Por esta razão, os níveis plasmáticos de proteína B do surfactante podem ajudar a avaliar os pacientes com problemas cardíacos, diminuindo a estabilidade da membrana alvéolo-capilar. Neste estudo, os níveis plasmáticos deste biomarcador foram medidos nos períodos pré-operatório e pós-operatório. Este estudo foi realizado para detectar as diferenças entre pacientes hipertensos e normotensos em nível pulmonar. As diferenças antes e depois da circulação extracorpórea foram examinadas. Resultados: As diferenças no tempo de circulação extracorpórea, tempo de pinçamento, a dose de drogas vasoativas, e a duração da terapia intensiva de pacientes com e sem hipertensão pulmonar foram estatisticamente significativas (P<0,05). Os resultados revelaram que este estado fisiopatológico foi relacionado a outras variáveis que foram estudadas. Acreditamos que as diferenças nos níveis de SPB pré-operatório e pós-operatório pode ser atribuída a danos na membrana alvéolo-capilar e disfunção do surfactante alveolar. Descobrimos que esta condição fisiopatológica foi significativamente associada com parâmetros pós-operatórios. Conclusão: Os resultados do estudo mostraram que a proteína B surfactante estava presente no sangue de pacientes com doença cardíaca congênita no pré-operatório. Longos tempos de circulação extracorpórea podem exercer danos na membrana alvéolo-capilar em pacientes com ...

Opposite behavior of plasma levels surfactant protein type B and receptor for advanced glycation end products in pulmonary sarcoidosis.

BACKGROUND: No biological marker is currently available for evaluating pulmonary involvement and/or for monitoring the clinical course of sarcoidosis. The present pilot study focused on possible relationships between circulating plasma levels of surfactant protein type B (SP-B) and plasma receptor for advanced glycation end products (RAGE) and lung function abnormalities in patients with pulmonary sarcoidosis, since both SP-B and RAGE have been previously suggested as lung injury markers. The plasmatic levels of these two proteins were also investigated with respect to functional capacity, as assessed by a cardiopulmonary exercise test (CPET). METHODS: Thirty pulmonary sarcoidosis outpatients and fifteen volunteers (Control Group) underwent lung function tests and CPET. Resting SP-B and RAGE plasma levels were also determined. Patients were then categorized according to the severity of their pulmonary involvement, as assessed in terms of lung diffusion for carbon monoxide (DLCO) values. RESULTS: Group B showed SP-B levels higher and RAGE levels lower than Group A and Control Group (p < 0.01). Group A showed lower RAGE levels than Control Group (p < 0.01), whereas SP-B levels did not differ between these two groups. A significant univariate relationship was found between both SP-B and RAGE and several lung function data, particularly with DLCO (SP-B Vs DLCO: r: -0.437, p = 0.016; RAGE Vs DLCO: r: -0.451, p = 0.012). CONCLUSIONS: Circulating plasma levels of SP-B and RAGE showed an opposite behavior in patients with pulmonary sarcoidosis. SP-B values are directly related to alveolar unit damage, supporting a possible role of SP-B as a marker of disease severity in these patients. Differently, RAGE decreases in severe sarcoidosis, suggesting more complex underlying mechanisms.

Serum amyloid A in uremic HDL promotes inflammation.

Uremia impairs the atheroprotective properties of HDL, but the mechanisms underlying why this occurs are unknown. Here, we observed that HDL isolated from healthy individuals inhibited the production of inflammatory cytokines by peripheral monocytes stimulated with a Toll-like receptor 2 agonist. In contrast, HDL isolated from the majority of patients with ESRD did not show this anti-inflammatory property; many HDL samples even promoted the production of inflammatory cytokines. To investigate this difference, we used shotgun proteomics to identify 49 HDL-associated proteins in a uremia-specific pattern. Proteins enriched in HDL from patients with ESRD (ESRD-HDL) included surfactant protein B (SP-B), apolipoprotein C-II, serum amyloid A (SAA), and α-1-microglobulin/bikunin precursor. In addition, we detected some ESRD-enriched proteins in earlier stages of CKD. We did not detect a difference in oxidation status between HDL isolated from uremic and healthy patients. Regarding function of these uremia-specific proteins, only SAA mimicked ESRD-HDL by promoting inflammatory cytokine production. Furthermore, SAA levels in ESRD-HDL inversely correlated with its anti-inflammatory potency. In conclusion, HDL has anti-inflammatory activities that are defective in uremic patients as a result of specific changes in its molecular composition. These data suggest a potential link between the high levels of inflammation and cardiovascular mortality in uremia.

Interactions between smoking, pulmonary surfactant protein B, and atherosclerosis in the general population: the Dallas Heart Study.

OBJECTIVE: Pulmonary surfactant protein B (SP-B), an alveolar protein normally detectable at only very low concentrations in blood, circulates at higher levels among smokers and those with alveolar injury and inflammation. We hypothesized that SP-B may serve as a marker of the vascular effects of smoking and would thus be associated with subclinical measures of atherosclerosis. METHODS AND RESULTS: Plasma levels of SP-B were measured in 3294 subjects, ages 30 to 65, enrolled in the Dallas Heart Study, a probability-based population sample of Dallas County adults. Coronary artery calcium (CAC) was measured by computed tomography and abdominal aortic plaque (AP) by magnetic resonance imaging. The cohort comprised 29% current and 17% former smokers. The overall prevalence of CAC was 22%, and that of AP was 39%. Median SP-B levels were 5-fold higher among current versus never smokers (P<0.0001) and were significantly correlated with estimated pack-years smoked (Spearman ρ=0.35, P<0.0001). Increasing levels of SP-B also associated with other traditional cardiac risk factors and higher levels of inflammatory biomarkers. In univariable analyses, increasing SP-B quartiles associated with higher prevalence of both CAC and AP (P(trend)<0.0001 for each). In multivariable analyses adjusting for traditional cardiovascular risk factors, SP-B remained associated with AP (OR 1.87 for the 4th versus 1st quartiles, 95% confidence interval 1.39 to 2.51; P<0.0001) but not CAC. An interaction was observed between SP-B, smoking status, and AP (P(interaction)=0.01), such that SP-B associated with AP in current smokers (adjusted OR 2.15 for the 4th versus 1st quartile, 95% confidence interval 1.26 to 3.67; P=0.005) but not in former or never smokers. CONCLUSIONS: Circulating levels of SP-B increase with greater smoking burden and independently associate with abdominal AP among current smokers. Our findings support further investigation of the role of SP-B as a marker of the vascular effects of smoking.

Kinetics of plasma SPB and RAGE during mechanical ventilation in patients undergoing major vascular surgery.

Receptor-of-Advanced-Glycation-End-products (RAGE) and Surfactant-Protein-type-B (SPB) are reported as lung injury markers. Unlike SPB, RAGE is secreted by several tissues, so that RAGE specificity as lung injury marker is questionable. We measured SPB and RAGE in 19 patients undergoing major vascular abdominal surgery. SPB and RAGE were measured before mechanical ventilation (T0), at 1st (T1), 2nd (T2) and, when present, 3rd (T3) hour of mechanical ventilation, and 1h after extubation (T(POST)). Last data during mechanical ventilation, either T2 or T3, are reported as T(END). SPB and RAGE values were normalized for total protein (SPB(N) and RAGE(N)). SPB(N) and RAGE(N) increments from T0 to T(END) were 56.2 [39.1] ng/mg (mean [75-25 percentile]) and 10.6[7.1] pg/mg, respectively. SPB values increased progressively during mechanical ventilation, whereas RAGE values increased at T(1) but not thereafter. SPB(N) increase (T(END)-T0), but not RAGE(N), was related to ΔPaO(2)/FiO2 changes during mechanical ventilation (r=0.575, p=0.01). Plasma RAGE(N) and SPB(N) kinetics in patients undergoing major vascular surgery are different.

[Importance of surfactant proteins B and D for the differential diagnosis of acute dyspnea]. / Bedeutung der Surfactant-Proteine B und D in der Differentialdiagnostik der akuten Dyspnoe.

BACKGROUND AND PURPOSE: The basis for an optimal therapy of cardiopulmonary diseases is the assessment of an early diagnosis. This implies an evaluation of possible differential diagnoses of acute dyspnea. In numerous studies, natriuretic peptides were characterized as additional, meaningful parameters for the assessment of left ventricular function. Current studies could demonstrate that surfactant proteins B (SP-B) and D (SP-D) are of importance for the differentiation of patients with acute dyspnea. The aim of this study was to compare the values of NT-proBNP (N-terminal brain natriuretic peptide) and surfactant proteins for the assessment of a final diagnosis in patients with acute dyspnea. PATIENTS AND METHODS: NT-proBNP, SP-B and SP-D were measured in 81 patients with acute dyspnea in the emergency room and were correlated with clinical and echocardiographic parameters with respect to the final diagnosis. For this, patients were classified with respect to clinical and echocardiographic parameters in different subgroups concerning the final diagnosis of acute dyspnea. RESULTS: In patients with a cardiac origin of acute dyspnea, plasma levels of NT-proBNP were significantly higher as compared to patients with a noncardiac diagnosis (p = 0.04). SP-D was highest in patients with a cardiac origin of acute dyspnea, but after performing regression analysis it seems to be of less importance for the differential diagnosis of acute dyspnea as compared to NT-proBNP. SP-B plasma levels were not different between the four subgroups. CONCLUSION: NT-proBNP is of importance for the differential diagnosis of acute dyspnea. Although SP-D shows similar changes of plasma levels between the four subgroups, it seems to be of less importance for the differential diagnosis of acute dysnea. SP-B occurs to be of no relevance for the differentiation between cardiac and noncardiac origin of acute dyspnea.

Circulating plasma surfactant protein type B as biological marker of alveolar-capillary barrier damage in chronic heart failure.

BACKGROUND: Surfactant protein type B (SPB) is needed for alveolar gas exchange. SPB is increased in the plasma of patients with heart failure (HF), with a concentration that is higher when HF severity is highest. The aim of this study was to evaluate the relationship between plasma SPB and both alveolar-capillary diffusion at rest and ventilation versus carbon dioxide production during exercise. METHODS AND RESULTS: Eighty patients with chronic HF and 20 healthy controls were evaluated consecutively, but the required quality for procedures was only reached by 71 patients with HF and 19 healthy controls. Each subject underwent pulmonary function measurements, including lung diffusion for carbon monoxide and membrane diffusion capacity, and maximal cardiopulmonary exercise test. Plasma SPB was measured by immunoblotting. In patients with HF, SPB values were higher (4.5 [11.1] versus 1.6 [2.9], P=0.0006, median and 25th to 75th interquartile), whereas lung diffusion for carbon monoxide (19.7+/-4.5 versus 24.6+/-6.8 mL/mm Hg per min, P<0.0001, mean+/-SD) and membrane diffusion capacity (28.9+/-7.4 versus 38.7+/-14.8, P<0.0001) were lower. Peak oxygen consumption and ventilation/carbon dioxide production slope were 16.2+/-4.3 versus 26.8+/-6.2 mL/kg per min (P<0.0001) and 29.7+/-5.9 and 24.5+/-3.2 (P<0.0001) in HF and controls, respectively. In the HF population, univariate analysis showed a significant relationship between plasma SPB and lung diffusion for carbon monoxide, membrane diffusion capacity, peak oxygen consumption, and ventilation/carbon dioxide production slope (P<0.0001 for all). On multivariable logistic regression analysis, membrane diffusion capacity (beta, -0.54; SE, 0.018; P<0.0001), peak oxygen consumption (beta, -0.53; SE, 0.036; P=0.004), and ventilation/carbon dioxide production slope (beta, 0.25; SE, 0.026; P=0.034) were independently associated with SPB. CONCLUSIONS: Circulating plasma SPB levels are related to alveolar gas diffusion, overall exercise performance, and efficiency of ventilation showing a link between alveolar-capillary barrier damage, gas exchange abnormalities, and exercise performance in HF.

Pneumoproteins as markers of paraquat lung injury: a clinical case.

OBJECTIVE: To describe the changes in lung-specific secretory proteins in biological fluids in a fatal case of paraquat ingestion and to present immunostaining data obtained on postmortem lung tissue specimens. METHODS: A 20-year-old man committed suicide by ingesting 100ml of a 20% paraquat solution. Surfactant associated proteins A (SP-A), B (SP-B) and Clara cell 16kDa protein (CC16) were determined in the serum and on broncho-alveloar lavage performed 18h after admission. Renal failure progressed rapidly and the patient died from refractory hypoxia. Immunostaining studies using antibodies directed against CC16, SP-A and SP-B were performed on postmortem lung tissue specimens. RESULTS: Serum CC16 seemed to increase gradually with the progression of renal impairment. Serum SP-A and SP-B levels increased before any significant changes in pulmonary gas exchanges. The immunostaining study showed that the labeling for SP-A and SP-B was reduced or absent following paraquat toxicity, while Clara cells were relatively preserved. CONCLUSIONS: The elevation of serum CC16 with paraquat toxicity is probably mainly related to a reduced renal clearance. The increase of serum SP-A and SP-B could reflect an increased lung to blood leakage, independently of the alteration of the renal function.

Genetic determinants of C-reactive protein in COPD.

Chronic obstructive pulmonary disease (COPD) is associated with a systemic inflammatory state, marked by elevations in serum inflammatory markers including C-reactive protein (CRP). The present study sought to determine epidemiological predictors of CRP levels, to estimate the genetic influence on CRP levels, and to identify genetic variants that affect CRP in a family-based study of COPD. CRP was measured by a high-sensitivity assay in participants from the Boston Early-Onset COPD Study. Predictors of CRP level were determined using multilevel linear models. Variance component analysis was used to estimate heritability and to perform genome-wide linkage analysis for CRP levels. Two variants in the surfactant protein B (SFTPB) gene were tested for association with CRP levels. Increased age, female sex, higher body mass index, greater smoking pack-yrs and reduced forced expiratory volume in one second were all associated with increased CRP levels. There was a significant genetic influence on CRP (heritability = 0.25). Genome-wide linkage analysis revealed several potentially interesting chromosomal regions, though no significant evidence for linkage was found. A short tandem repeat marker near SFTPB was significantly associated with CRP levels. There is a genetic influence on C-reactive protein levels in chronic obstructive pulmonary disease patients. Preliminary evidence suggests an association of the surfactant protein B gene with systemic inflammation in chronic obstructive pulmonary disease.