Postmortem serum levels of pulmonary surfactant-associated proteins A and D with regard to the cause of death in medicolegal autopsy

AbstractAccurate blood-borne biomarkers are sought for diagnosis, prognosis and treatment stratification. Consistent handling of blood is essential for meaningful data interpretation, however, delays during processing are occasionally unavoidable. We investigated the effects of immediately placing blood samples on ice versus room temperature for 1 h (reference protocol), and holding samples on ice versus room temperature during a 3 h delay to processing. Using Luminex multi-plex assays to assess cytokines (n = 29) and diabetes-associated proteins (n = 15) in healthy subjects, we observed that placing blood samples immediately on ice decreased the serum levels of several cytokines, including PAI-1, MIP1-β, IL-9, RANTES and IL-8. During a delay to processing, some analytes, e.g. leptin and insulin, showed little change in serum or plasma values. However, for approximately half of the analytes studied, a delay, regardless of the holding temperature, altered the measured levels compared to the reference protocol. Effects differed between serum and plasma and for some analytes the direction of change in level varied across individuals. The optimal holding temperature for samples during a delay was analyte-specific. In conclusion, deviations from protocol can lead to significant changes in blood analyte levels. Where possible, protocols for blood handling should be pre-determined in an analyte-specific manner.

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Vitamin K-dependent carboxylation of pulmonary surfactant-associated proteins.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.84.16.5952 ◽

1987 ◽

Vol 84 (16) ◽

pp. 5952-5956 ◽

Cited By ~ 13

Author(s):

S. R. Rannels ◽

K. J. Gallaher ◽

R. Wallin ◽

D. E. Rannels

Keyword(s):

Vitamin K ◽

Pulmonary Surfactant ◽

Associated Proteins

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Structural characteristics and intermolecular organization of human pulmonary-surfactant-associated proteins

Biochemical Journal ◽

10.1042/bj2400107 ◽

1986 ◽

Vol 240 (1) ◽

pp. 107-114 ◽

Cited By ~ 14

Author(s):

S W Crawford ◽

R P Mecham ◽

H Sage

Keyword(s):

Pulmonary Surfactant ◽

Peptide Mapping ◽

Structural Characteristics ◽

Three Dimensional ◽

Lavage Fluid ◽

Clinical Syndrome ◽

Structural Relationships ◽

Associated Proteins ◽

Cross Links ◽

Covalently Linked

The structural relationships and intermolecular organization among the proteins associated with pulmonary surfactant are largely unknown. We studied the pulmonary-surfactant-associated proteins in the bronchoalveolar lavage fluid obtained from a patient with the clinical syndrome of alveolar proteinosis. The major proteins with Mr values of 32,000-36,000 and 62,000 formed thiol-dependent complexes (Mr greater than 400,000) with intermolecular disulphide bonds present in the collgenase-sensitive domains of these proteins. In contrast, other proteins, which were collagenase-insensitive, formed thiol-dependent oligomers that were not covalently linked to the major proteins. The associations of these proteins in the surfactant of a normal individual were similar. By amino acid analysis, two-dimensional peptide mapping and bacterial-collagenase digestion the 32,000-36,000-Mr and 62,000-Mr proteins were nearly identical. Differences in CNBr cleavage products suggested that the larger of the proteins was formed by non-disulphide, covalent, cross-links in the collagenase-sensitive domains of the 32,000-36,000-Mr proteins. Thus the evidence suggested that the lipid-associated proteins of Mr 32,000-36, 000 contained both disulphide and non-disulphide cross-links in the collagen-like N-terminal region of the proteins and form higher-Mr complexes. This organization may support the three-dimensional conformation of surfactant in the alveolar space.

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Surfactants in the Management of Respiratory Distress Syndrome in Extremely Premature Infants

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-11.3.132 ◽

2006 ◽

Vol 11 (3) ◽

pp. 132-144

Author(s):

Rangasamy Ramanathan

Keyword(s):

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Pulmonary Surfactant ◽

Randomized Clinical Trials ◽

Distress Syndrome ◽

Surfactant Therapy ◽

Synthetic Surfactant ◽

Associated Proteins ◽

Natural Surfactants ◽

Synthetic Surfactants

Respiratory distress syndrome (RDS) is primarily due to decreased production of pulmonary surfactant, and it is associated with significant neonatal morbidity and mortality. Exogenous pulmonary surfactant therapy is currently the treatment of choice for RDS, as it demonstrates the best clinical and economic outcomes. Studies confirm the benefits of surfactant therapy to include reductions in mortality, pneumothorax, and pulmonary interstitial emphysema, as well as improvements in oxygenation and an increased rate of survival without bronchopulmonary dysplasia. Phospholipids (PL) and surfactant-associated proteins (SP) play key roles in the physiological activity of surfactant. Different types of natural and synthetic surfactant preparations are currently available. To date, natural surfactants demonstrate superior outcomes compared to the synthetic surfactants, at least during the acute phase of RDS. This disparity is often attributed to biochemical differences including the presence of surfactant-associated proteins in natural products that are not found in the currently available synthetic surfactants. Comparative trials of the natural surfactants strive to establish the precise differences in clinical outcomes among the different preparations. As new surfactants become available, it is important to evaluate them relative to the known benefits of the previously existing surfactants. In order to elucidate the role of surfactant therapy in the management of RDS, it is important to review surfactant biochemistry, pharmacology, and outcomes from randomized clinical trials.

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Localization of Misprocessed Pulmonary Surfactant Protein C in Tubular Myelin Enriched Fractions By Cryo Immunogold Labeling

Microscopy and Microanalysis ◽

10.1017/s1431927600036837 ◽

2000 ◽

Vol 6 (S2) ◽

pp. 868-869

Author(s):

C.-L. Na ◽

E. A. Evans ◽

H. T. Akinbi ◽

T. E. Weaver

Keyword(s):

Pulmonary Surfactant ◽

Protein C ◽

Intracellular Localization ◽

Surfactant Protein ◽

Biologically Active ◽

Alveolar Type ◽

Double Knockout ◽

Surfactant Protein C ◽

Associated Proteins ◽

Pulmonary Surfactant Protein

Pulmonary surfactant is secreted by alveolar type II cells and reduces the surface tension at the air-liquid interface of alveoli. After pulmonary surfactant is secreted into the alveolar space, it transforms into tubular myelin, a highly ordered 3-dimensional lattice-like structure. Pulmonary surfactant protein C (SP-C), one of four pulmonary surfactant associated proteins, is synthesized as a proprotein which is processed to biologically active 35 amino acid mature peptide by proteolytic cleavage of N- and C-terminal peptides from the SP-C propeptide (Weaver, 1998). Processing of SP-C is linked to the expression of pulmonary surfactant protein B (SP-B): In SP-B deficient mice, SP-C is misprocessed and present in the bronchoalveolar lavage (BAL; Vorbroker et. al., 1995a). Although the intracellular localization of SP-C is well established (Vorbroker et. al., 1995b), there is no ultrastructure study available regarding the localization of misprocessed SP-C in the airway. In this study, we used transgenic mice expressing a truncated human SP-B propeptide (hSP-BΔC+/+) bred into the murine granulocyte macrophage colony stimulating factor (GMCSF) and SP-B double knockout background (hSP-BΔC+/+: GMCSF-/-: mSP-B-/-) as a model to localize the misprocessed SP-C by cryoimmunogold labeling.

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Inflammatory Profile and Response to Anti-Tumor Necrosis Factor Therapy in Patients with Chronic Pulmonary Sarcoidosis

Clinical and Vaccine Immunology ◽

10.1128/cvi.00337-10 ◽

2011 ◽

Vol 18 (6) ◽

pp. 931-939 ◽

Cited By ~ 33

Author(s):

Matthew J. Loza ◽

Carrie Brodmerkel ◽

Roland M. Du Bois ◽

Marc A. Judson ◽

Ulrich Costabel ◽

...

Keyword(s):

Clinical Trial ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Serum Levels ◽

Unknown Etiology ◽

Infliximab Treatment ◽

Tnf Α ◽

Associated Proteins ◽

Inflammatory Profile ◽

Necrosis Factor

ABSTRACTSarcoidosis is an inflammatory, granulomatous disease of unknown etiology that most commonly afflicts the lungs. Despite aggressive immunosuppressive therapies, many sarcoidosis patients still chronically present significant symptoms. Infliximab, a therapeutic tumor necrosis factor alpha (TNF-α) monoclonal antibody (MAb), produced a small but significant improvement in forced vital capacity (FVC) in sarcoidosis patients in a double-blind, placebo-controlled, phase II clinical trial. In the current study, serum samples from this clinical trial were assessed to evaluate the underlying hypothesis that treatment with infliximab would reduce systemic inflammation associated with sarcoidosis, correlating with the extent of clinical response. A 92-analyte multiplex panel was used to assess the expression of serum proteins in 134 sarcoidosis patients compared with sera from 50 healthy controls. A strong systemic inflammatory profile was associated with sarcoidosis, with 29 analytes significantly elevated in sarcoidosis (false-discovery rate, <0.05 and >50% higher than controls). The associated analytes included chemokines, neutrophil-associated proteins, acute-phase proteins, and metabolism-associated proteins. This profile was evident despite patients receiving corticosteroids and immunosuppressive therapies. Following infliximab treatment, sarcoidosis patients expressing the highest levels of TNF-α, who had more severe disease, had the greatest improvement in FVC and reduction in serum levels of the inflammatory proteins MIP-1β and TNF-RII. This study supports the need for further exploration of anti-TNF therapy for chronic sarcoidosis patients, particularly for those expressing the highest serum levels of TNF-α.

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Pulmonary surfactant-associated proteins: their role in surface tension reduction

The Surfactant System of the Lung ◽

10.1007/978-1-349-12553-1_2 ◽

1991 ◽

pp. 7-17

Author(s):

Fred Possmayer ◽

Amanda Cockshutt ◽

Shou-Hwa Yu

Keyword(s):

Surface Tension ◽

Pulmonary Surfactant ◽

Tension Reduction ◽

Surface Tension Reduction ◽

Associated Proteins

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Physiological and inflammatory response to instillation of an oxidized surfactant in a rat model of surfactant deficiency

Journal of Applied Physiology ◽

10.1152/japplphysiol.01143.2003 ◽

2004 ◽

Vol 96 (5) ◽

pp. 1674-1680 ◽

Cited By ~ 13

Author(s):

Timothy C. Bailey ◽

Keith A. Da Silva ◽

James F. Lewis ◽

Karina Rodriguez-Capote ◽

Fred Possmayer ◽

...

Keyword(s):

Inflammatory Response ◽

Physiological Response ◽

Pulmonary Surfactant ◽

Pulmonary Inflammation ◽

Physiological Effect ◽

Mechanically Ventilated ◽

Alveolar Surfactant ◽

Associated Proteins ◽

Surfactant Preparation

Pulmonary surfactant is a mixture of phospholipids (∼90%) and surfactant-associated proteins (SPs) (∼10%) that stabilize the lung by reducing the surface tension. One proposed mechanism by which surfactant is altered during acute lung injury is via direct oxidative damage to surfactant. In vitro studies have revealed that the surface activity of oxidized surfactant was impaired and that this effect could be overcome by adding SP-A. On the basis of this information, we hypothesized that animals receiving oxidized surfactant preparations would exhibit an inferior physiological and inflammatory response and that the addition of SP-A to the oxidized preparations would ameliorate this response. To test this hypothesis, mechanically ventilated, surfactant-deficient rats were administered either bovine lipid extract surfactant (BLES) or in vitro oxidized BLES of three doses: 10 mg/kg, 50 mg/kg, or 10 mg/kg + SP-A. When instilled with 10 mg/kg normal surfactant, the rats had a significantly superior arterial Po2 responses compared with the rats receiving oxidized surfactant. Interestingly, increasing the dose five times mitigated this physiological effect, and the addition of SP-A to the surfactant preparation had little impact on improving oxygenation. There were no differences in alveolar surfactant pools and the indexes of pulmonary inflammation between the 10 mg/kg dose groups, nor was there any differences observed between either of the groups supplemented with SP-A. However, there was significantly more surfactant and more inflammatory cytokines in the 50 mg/kg oxidized BLES group compared with the 50 mg/kg BLES group. We conclude that instillation of an in vitro oxidized surfactant causes an inferior physiological response in a surfactant-deficient rat.

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