Surfactant Protein D Concentrations Research Articles

Growth differentiation factor-15 and circulating biomarkers as predictors of periodontal treatment effects in patients with periodontitis: a randomized-controlled clinical trial

BackgroundDuring the last decades, in patients with periodontitis, periodontal treatment has been shown to reduce the potential release of local and systemic biomarkers linked to an early risk of systemic inflammatory disorders. This study evaluated the efficacy of non-surgical-periodontal treatment (NSPT) on growth differentiation factor 15 (GDF-15) and related circulating biomarkers such as glutathione peroxidase 1 (GPx-1), c-reactive protein (hs-CRP), and surfactant protein D (SP-D) in periodontal patients and explored whether subjects who had high GDF-15 levels at baseline showed increased clinical benefits following NSPT at 6-months follow-up.MethodsFor this two-arm, parallel randomized clinical trial, patients with periodontitis were randomly allocated to receive quadrant scaling and root-planing (Q-SRP, n = 23, median age 51 years old) or full-mouth disinfection (FMD, n = 23, median age 50 years old) treatment. Clinical and periodontal parameters were recorded in all enrolled patients. The primary outcome was to analyse serum concentrations changes of GDF-15 and of GPx-1, hs-CRP, and SP-D at baseline and at 30, 90, and 180-days follow-up after NSPT through enzyme-linked immunosorbent assay (ELISA) and nephelometric assay techniques.ResultsIn comparison with FMD, patients of the Q-SRP group showed a significant improvement in clinical periodontal parameters (p < 0.05) and a reduction in the mean levels of GDF-15 (p = 0.005), hs-CRP (p < 0.001), and SP-D (p = 0.042) and an increase of GPx-1 (p = 0.025) concentrations after 6 months of treatment. At 6 months of treatment, there was a significant association between several periodontal parameters and the mean concentrations of GDF-15, GPx-1, hs-CRP, and SP-D (p < 0.05 for all parameters). Finally, the ANOVA analysis revealed that, at 6 months after treatment, the Q-SRP treatment significantly impacted the reduction of GDF-15 (p = 0.015), SP-D (p = 0.026) and the upregulation of GPx-1 (p = 0.045).ConclusionThe results evidenced that, after 6 months of treatment, both NSPT protocols improved the periodontal parameters and analyzed biomarkers, but Q-SRP was more efficacious than the FMD approach. Moreover, patients who presented high baseline GDF-15 and SP-D levels benefited more from NSPT at 6-month follow-up.Trial registrationNCT05720481.

VITAMIN D3 AND Α-TOCOPHEROL ACETATE AMELIORATE INFLAMMATORY AND FIBROTIC PROCESSES IN SYSTEMIC SCLEROSIS: PRECLINICAL EVIDENCE

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vascular abnormalities. Despite extensive research, there is currently no effective treatment for SSc. This study aimed to investigate the effects of α-tocopherol acetate and vitamin D3 on the levels of surfactant protein D (SP-D), interleukin-13 (IL-13), and vascular cell adhesion molecule-1 (VCAM-1) in a preclinical model of SSc.&#x0D; The study included an intact group (IG) (15 animals) with no interventions, control group (CG) (20 animals) injected with isotonic solution, an experimental group #1 (EG#1) (25 animals) that were induced with SSc by injecting them subcutaneously with 0.5 ml of 5% (NaClO) three times a week for six consecutive weeks; and experimental group #2 (EG#2) (25 animals) with correction provided by injections of vitamin D (1000 IU / 100 g) and α-tocopherol acetate (10 mg / 100 g ) intramuscularly for 3 weeks.&#x0D; The serum concentrations of IL-13, SP-D, and VCAM-1 were significantly higher in the EG#1 compared to the control group (109.35 (93,23-199.05) vs 8.50 (5.60-14.20), p=0.004; 490.20 (156.20-605.70) vs 78.10 (40.80-100.40), p=0.004; 91.25 (85.00 -264.98) vs 19.50 (13.53-22.20), p=0.004 respectively). The administration of vitamin D3 and α-tocopherol acetate was found to have a positive effect on all three parameters investigated. The SP-D level in the EG#2 was significantly lower than that in the EG#1 (490.20 (156.20-605.70) vs 123.75 (108.80-145.03), p=0.004). The concentration of IL-13 and VCAM-1 were also lower in the EG#2.&#x0D; In conclusion, this study provides evidence of the beneficial effects of vitamin D3 and α-tocopherol acetate in reducing the levels of SP-D, IL-13, and VCAM-1 in a preclinical model of systemic sclerosis.

Surfactant protein D (SP-D) as a biomarker of SARS-CoV-2 infection

BackgroundSurfactant protein-D (SP-D) is a lung-resident protein that has emerged as a potential biomarker for COVID-19. Previous investigations on acute respiratory distress syndrome patients demonstrated a significant increment of SP-D serum levels in pathological conditions. Since SP-D is not physiologically permeable to alveoli-capillary membrane and poorly expressed by other tissues, this enhancement is likely due to an impairment of the pulmonary barrier caused by prolonged inflammation. MethodsA retrospective study on a relatively large cohort of patients of Hospital Pio XI of Desio was conducted to assess differences of the hematic SP-D concentrations among COVID-19 patients and healthy donors and if SP-D levels resulted a risk factor for disease severity and mortality. ResultsThe first analysis, using an ANOVA-model, showed a significant difference in the mean of log SP-D levels between COVID-19 patients and healthy donors. Significant variations were also found between dead vs survived patients. Results confirm that SP-D concentrations were significantly higher for both hospitalized COVID-19 and dead patients, with threshold values of 150 and 250 ng/mL, respectively. Further analysis conducted with Logistic Mixed models, highlighted that higher SP-D levels at admission and increasing differences among follow-up and admission values resulted the strongest significant risk factors of mortality (model predictive accuracy, AUC = 0.844). ConclusionsThe results indicate that SP-D can be a predictive marker of COVID-19 disease and its outcome. Considering its prognostic value in terms of mortality, the early detection of SP-D levels and its follow-up in hospitalized patients should be considered to direct the therapeutic intervention.

Lipidomic analysis of surfactant and plasma from horses with asthma and age-matched healthy horses.

To perform lipidomic analysis of surfactant and plasma from asthmatic and healthy horses. 30 horses with clinical signs of asthma and 30 age-matched control horses. Detailed history, physical examination, CBC, and bronchoalveolar lavage fluid (BALF) cytologies were obtained. Asthmatic horses were grouped based on their BALF inflammatory profile: severe equine asthma (SEA), mild equine asthma with neutrophilic airway inflammation (MEA-N), or mild equine asthma with eosinophilic airway inflammation (MEA-E). Each asthma group was assigned its own age-matched control group. Lipidomic analysis was completed on surfactant and plasma. Surfactant protein D (SP-D) concentrations were measured in serum and BALF. SEA surfactant was characterized by a phospholipid deficit and altered composition (increased ceramides, decreased phosphatidylglycerol, and increased cyclic phosphatidic acid [cPA]). In comparison, MEA-N surfactant only had a decrease in select phosphatidylglycerol species and increased cPA levels. The plasma lipidomic profile was significantly different in all asthma groups compared to controls. Specifically, all groups had increased plasma phytoceramide. SEA horses had increased plasma cPA and diacylglycerol whereas MEA-N horses only had increased cPA. MEA-E horses had increases in select ceramides and dihydrocermides. Only SEA horses had significantly increased serum SP-D concentrations. The most significant surfactant alterations were present in SEA (altered phospholipid content and composition); only mild changes were observed in MEA-N horses. The plasma lipidomic profile was significantly altered in all groups of asthmatic horses and differed among groups. Data from a larger population of asthmatic horses are needed to assess implications for diagnosis, prognosis, and treatment.

Refractory ceramic fibers induced changes in serum Clara cell protein 16 and surfactant protein D levels in rats

Objective: To explore the effect of refractory ceramic fibers (RCFs) on the serum Clara cell protein 16 (CC16) and surfactant protein D (SP-D) levels in Wistar rats. Methods: In October 2020, 96 healthy adult male Wistar rats were randomly divided into control group (equal volume of normal saline) , low-dose group (5 mg/ml RCFs) , medium-dose group (10 mg/ml RCFs) and high-dose group (20 mg/ml RCFs) , and subjected to non-exposure tracheal instillation. After intraperitoneal anesthesia, the rats were instilled with 200 μl of RCFs suspension or normal saline, once every 3 days for a total of 4 times. At 7, 14, 28, and 90 days after exposure, 6 rats were sacrificed by blood sampling through the abdominal aorta. The organs were separated, histopathological changes of lungs were observed and lung injury scores were performed. The contents of serum CC16 and SP-D were determined by enzyme-linked immunosorbent assay (ELISA) . Results: RCFs could cause inflammatory cells in rat lung tissues, widening of the lung septum and destruction of alveolar structure. 7 days after exposure, the lung injury scores of rats in each dose group were higher than control group, and the lung injury score of the high-dose group was higher than low-dose group (P<0.05) . 14 and 90 days after exposure, the lung injury scores of the medium-dose and high-dose groups were higher than control group (P<0.05) . 28 days after exposure, the lung injury score of the high-dose group was higher than control group (P<0.05) . 7 days after exposure, the serum CC16 and SP-D concentrations of rats in the medium-dose and high-dose groups were significantly higher than control and low-dose groups (P<0.05) . 28 days after exposure, the serum CC16 concentrations of rats in the low-dose and medium-dose groups were significantly lower than those of the control and high-dose groups (P<0.05) . After 90 days of exposure, the serum CC16 concentrations of rats decreased with the increase of the exposure dose (F=28.853, P<0.01) , and the concentrations of SP-D increased with the increase of the exposure dose (F=25.636, P<0.01) . Conclusion: RCFs exposure may cause certain damage to rat Clara cells and alveolar-capillary barrier. The severity of lung injury can be indirectly understood through the dynamic changes of serum CC16 and SP-D.

Surfactant protein D concentration in a pediatric population with suspected sleep disorder.

Obstructive sleep apnea (OSA) affects between 2% and 4% in children and there is a search for new biomarkers that can be useful both in the diagnosis and in the evolution of the disease. The surfactant protein D (SP-D) is a collection that is part of the innate immune system exerting an anti-inflammatory and antimicrobial effect. Thus, the objective of this study was to evaluate the concentration of SP-D in the suspect OSA pediatric population. A total of 178 children were recruited in this prospective study. Blood samples, sleep parameters, feeding habits, anthropometric, sociodemographic, and family data were collected. Specific biochemical determinations were made, and the plasmatic concentrations of SP-D were measured by enzyme-linked immunosorbent assay. We found no statistical correlation between the SP-D concentration and the apnea-hypopnea index (AHI) from the data. Nevertheless, the changes in SP-D levels could be correlated to a large extent by the arousals that often go along with hypopneas (r = -0.258, p = 0.011 unadjusted; r = -0.258, p = 0.014 adjusted by age and body mass inded [BMI] Z-score). Intermittent hypoxia was correlated with C-reactive protein levels (r = 0.547, p < 0.001 unadjusted; r = 0.542, p < 0.001 adjusted by age and BMI Z-score). Although AHI and SP-D did not appear to correlate, a secondary analysis suggests that sleep fragmentation, which is produced by arousals, may do, and further research is needed to determine the mechanisms by which changes in SP-D occur in OSA.

Biomarkers in premature calves with and without respiratory distress syndrome.

BackgroundApproaches to the evaluation of pulmonary arterial hypertension (PAH) in premature calves by using lung‐specific epithelial and endothelial biomarkers are needed.ObjectiveTo investigate the evaluation of PAH in premature calves with and without respiratory distress syndrome (RDS) by using lung‐specific epithelial and endothelial biomarkers and determine the prognostic value of these markers in premature calves.AnimalsFifty premature calves with RDS, 20 non‐RDS premature calves, and 10 healthy term calves.MethodsHypoxia, hypercapnia, and tachypnea were considered criteria for RDS. Arterial blood gases (PaO2, PaCO2, oxygen saturation [SO2], base excess [BE], and serum lactate concentration) were measured to assess hypoxia. Serum concentrations of lung‐specific growth differentiation factor‐15 (GDF‐15), asymmetric dimethylarginine (ADMA), endothelin‐1 (ET‐1), vascular endothelial growth factor (VEGF), and surfactant protein D (SP‐D) were measured to assess PAH.ResultsArterial blood pH, PaO2, SO2, and BE of premature calves with RDS were significantly lower and PaCO2 and lactate concentrations higher compared to non‐RDS premature and healthy calves. The ADMA and SP‐D concentrations of premature calves with RDS were lower and serum ET‐1 concentrations higher than those of non‐RDS premature and healthy calves. No statistical differences for GDF‐15 and VEGF were found among groups.Conclusions and Clinical ImportanceSignificant increases in serum ET‐1 concentrations and decreases in ADMA and SP‐D concentrations highlight the utility of these markers in the diagnosis of PAH in premature calves with RDS. Also, we found that ET‐1 was a reliable diagnostic and prognostic biomarker for PAH and predicting mortality in premature calves.

Short Communication: A Pilot Study of the Effects of Losartan Versus Placebo on Pneumoproteins in HIV: A Secondary Analysis of a Randomized Double Blind Study.

HIV is an independent risk factor for lung disease, including chronic obstructive pulmonary disease (COPD) and emphysema. Angiotensin receptor blockers may be beneficial in COPD and emphysema through pathways that have been implicated in HIV-related lung disease. We performed a randomized comparison of the effects of losartan versus placebo on the plasma concentrations of the pneumoproteins, surfactant protein D (SPD) and club cell secretory protein (CCSP), in people living with HIV (PLWH). A total of 108 PLWH were included (52 assigned to losartan and 56 assigned to placebo). We found no difference in the change from baseline in log2 concentrations of CCSP or SPD over 1 year of follow-up. For SPD, we found a strong interaction by CD4+ counts, where those with CD4+ counts >350 cells/mm3 treated with losartan had more reduction (improvement) in SPD concentration than those treated with placebo (p value for interaction <.001). In conclusion, we did not find a beneficial effect of losartan on pneumoprotein concentrations in PLWH, but PLWH with higher CD4+ counts may have improvement in SPD when treated with losartan.

Surfactant protein D concentrations in serum and bronchoalveolar lavage fluid from young healthy horses on pasture and in a barn environment.

To evaluate surfactant protein D (SP-D) concentrations in serum and bronchoalveolar lavage fluid (BALF) from young healthy horses on pasture or housed in a typical barn. 20 young healthy horses. Horses were randomly assigned to 1 of 2 groups (pasture, n = 10; barn, 10), and serum and BALF samples were collected for SP-D determination at baseline (all horses on pasture) and 2 weeks and 4 weeks after the barn group of horses was relocated from the pasture to the barn. Other evaluations included physical and tracheoscopic examinations. Findings were compared within and between groups. Physical and tracheoscopic examinations, CBC, and serum biochemical analysis did not reveal evidence of respiratory disease, and no significant differences were present within and between groups. Serum SP-D concentrations did not significantly differ within and between groups, but BALF SP-D concentrations were significantly lower for the barn group at 2 weeks but not at 4 weeks, compared with baseline. The BALF SP-D concentration-to-BALF total protein concentration ratio was < 1.5 and did not significantly differ within and between groups. A mild decrease was evident in the concentration of SP-D in the BALF collected from young healthy horses after 2 weeks of exposure to a barn environment. The clinical importance of this finding remains to be determined.

Lung injury induced by short-term mechanical ventilation with hyperoxia and its mitigation by deferoxamine in rats

BackgroundLong-term mechanical ventilation with hyperoxia can induce lung injury. General anesthesia is associated with a very high incidence of hyperoxaemia, despite it usually lasts for a relatively short period of time. It remains unclear whether short-term mechanical ventilation with hyperoxia has an adverse impact on or cause injury to the lungs. The present study aimed to assess whether short-term mechanical ventilation with hyperoxia may cause lung injury in rats and whether deferoxamine (DFO), a ferrous ion chelator, could mitigate such injury to the lungs and explore the possible mechanism.MethodsTwenty-four SD rats were randomly divided into 3 groups (n = 8/group): mechanical ventilated with normoxia group (MV group, FiO2 = 21%), with hyperoxia group (HMV group, FiO2 = 90%), or with hyperoxia + DFO group (HMV + DFO group, FiO2 = 90%). Mechanical ventilation under different oxygen concentrations was given for 4 h, and ECG was monitored. The HMV + DFO group received continuous intravenous infusion of DFO at 50 mg•kg− 1•h− 1, while the MV and HMV groups received an equal volume of normal saline. Carotid artery cannulation was carried out to monitor the blood gas parameters under mechanical ventilation for 2 and 4 h, respectively, and the PaO2/FiO2 ratio was calculated. After 4 h ventilation, the right anterior lobe of the lung and bronchoalveolar lavage fluid from the right lung was sampled for pathological and biochemical assays.ResultsPaO2 in the HMV and HMV + DFO groups were significantly higher, but the PaO2/FiO2 ratio were significantly lower than those of the MV group (all p < 0.01), while PaO2 and PaO2/FiO2 ratio between HMV + DFO and HMV groups did not differ significantly. The lung pathological scores and the wet-to-dry weight ratio (W/D) in the HMV and HMV + DFO groups were significantly higher than those of the MV group, but the lung pathological score and the W/D ratio were reduced by DFO (p < 0.05, HMV + DFO vs. HMV). Biochemically, HMV resulted in significant reductions in Surfactant protein C (SP-C), Surfactant protein D (SP-D), and Glutathion reductase (GR) levels and elevation of xanthine oxidase (XOD) in both the Bronchoalveolar lavage fluid and the lung tissue homogenate, and all these changes were prevented or significantly reverted by DFO.ConclusionsMechanical ventilation with hyperoxia for 4 h induced oxidative injury of the lungs, accompanied by a dramatic reduction in the concentrations of SP-C and SP-D. DFO could mitigate such injury by lowering XOD activity and elevating GR activity.

Improving risk-stratification of rheumatoid arthritis patients for interstitial lung disease.

ObjectiveTo determine the performance of 3 circulating markers for the diagnosis and the progression of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA).MethodsSerum concentrations of 3 circulating markers, lung epithelial-derived surfactant protein D (SPD), chemokine CCL-18 and Krebs von den Lungen-6 glycoprotein (KL-6), were measured by ELISA in consecutive patients with established RA. These patients were recruited from 3 tertiary centers and they all had been investigated by chest high-resolution computed tomography (HRCT). For a subset of French patients, a follow-up HRCT was available (mean interval between HRCT: 3±1.5 years).ResultsAmong the 147 included patients (age: 66 ± 12 years, 69% women, disease duration 11 ± 10 years), 40 (27%) had RA-ILD on chest HRCT. SPD, CCL18 and KL-6 concentrations were significantly higher in patients with RA-ILD. ROC curve analysis to assess the diagnostic abilities of the three markers for the diagnosis of RA-ILD showed a superiority of KL-6 (Area under the curve, AUC: 0.79 95% CI 0.72–0.86) compared to SPD (AUC: 0.66 95% CI 0.58–0.74) and CCL18 (AUC: 0.62, 95% CI 0.53–0.70). The sensitivity of KL-6 for the diagnosis of RA-ILD was 68% with a specificity of 83%. The combination of KL-6 with SPD and CCL18 improved its diagnostic ability, with increased sensitivity from 68% to 77%, specificity from 83% to 97%. Increased KL-6 levels were independently associated with the presence of RA-ILD after the adjustment on other RA-ILD risk factors. In the French subset with longitudinal data, baseline KL-6 serum levels were predictive of ILD progression and the degree of ILD progression on HRCT was proportional to baseline KL-6 concentrations.ConclusionThese results show that KL-6 is a relevant circulating marker for the diagnosis and might be an interesting marker for the progression of RA-ILD.

Pneumoproteins in Offshore Drill Floor Workers.

The aim was to assess pneumoproteins and a certain biomarker of systemic inflammation in drill floor workers exposed to airborne contaminants generated during drilling offshore, taking into consideration serum biomarkers of smoking, such as nicotine (S-Nico) and cotinine. Blood samples of club cell protein 16 (CC-16), surfactant protein D (SP-D) and C-reactive protein (CRP) were collected before and after a 14-day work period from 65 drill floor workers and 65 referents. Air samples of oil mist, drilling mud components and elemental carbon were collected in person. The drill floor workers were exposed to a median air concentration of 0.18 mg/m3 of oil mist and 0.14 mg/m3 of airborne mud particles. There were no differences in the concentrations of CC-16 and SP-D across the 14-day work period and no difference between drill floor workers and referents at baseline after adjusting for differences in sampling time and smoking. CRP decreased across the work period. There was a strong association between the CC-16 concentrations and the time of sampling. Current smokers with S-Nico > detection limit (DL) had a statistically significantly lower CC-16 concentration, while smokers with S-Nico < DL had CC-16 concentrations similar to that of the non-smokers. Fourteen days of work offshore had no effect on serum pneumoprotein and CRP concentrations. However, the time of blood sampling was observed to have a strong effect on the measured concentrations of CC-16. The effect of current smoking on the CC-16 concentrations appears to be dependent on the S-Nico concentrations.

Serum concentration of surfactant protein D in patients with systemic sclerosis: The potential marker of the interstitial lung disease severity.

Pulmonary involvement is a severe manifestation of systemic sclerosis (SSc). The study was designed to determine the serum level of surfactant protein D (SP-D) in patients with SSc in relation to clinical and laboratory parameters as well as to analyze dynamics of changes of these indices within one year of observation. SP-D was assayed in 41 patients with SSc and 15 healthy controls. Additionally, pulmonary function tests, chest high-resolution computed tomography (HRCT), and inflammatory markers were assessed. All tests were performed twice: at entry and repeated after one year of observation. The serum level of SP-D was significantly higher in patients with SSc than in healthy controls. Serum concentration of SP-D was significantly higher in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD) than in those without SSc-ILD. SP-D was found to correlate with lung involvement evaluated with the Medsger score (diffusing capacity of the lung for carbon monoxide (DLCO), forced vital capacity, radiological changes, and estimated pressure in the pulmonary artery in echocardiography). SP-D correlated with the honeycombing and/or reticular pattern in HRCT and ground glass opacification pattern. Serum concentration of SP-D was elevated in patients with a decreased DLCO. Furthermore, SP-D was higher in patients with diffuse cutaneous type (dcSSc) of the disease than in those with SSc limited type (lcSSc). Because of the small size of the group, it was not possible to perform a statistical analysis for patients who had different results in HRCT, VC, and Medsger score between the first and the second evaluation. SP-D seems to be an index for assessing lung involvement. It reflects the state of pulmonary fibrosis but not the dynamics of the pulmonary fibrosis progression. Further studies are needed to evaluate clinical application of the index, and currently, there is no evidence for the recommendation of the application of SP-D in routine evaluation of patients with SSc.

Anti-inflammatory and regenerative effects of hypoxic signaling inhibition in a model of COPD

The aim of this study was to investigate anti-inflammatory and regenerative effects of inhibited activation of hypoxic signaling in COPD model using cyclooxygenase-2 (COX-2)-dependent pro-inflammatory cascade inhibition. Methods. COPD was modelled in rats by nitrogen dioxide (NO2, 30-40 mg×m –3 ) exposure for 90 days. Celecoxib was used as COX-2 inhibitor. The study group rats were given celecoxib (25 mg×kg –1 ) through an esophageal probe after 30 days of exposure. Control rats were given saline solution. The group 3 rats were intact. The rats were put out of the experience using cervical dislocation after 60 and 90 days of NO2 exposure. Bronchoalveolar lavage fluid (BALF) cytology was analyzed. COX-2, hypoxia-inducible factor-1α (HIF-1α), interleukin-17 (IL-17), and surfactant protein D (SP-D) were measured in BALF using ELISA method. Histological examination of the lung tissue was also performed. Results. 90-day exposure of NO2 resulted in 7.7-fold increase in BALF neutrophil count compared to that in intact rats. Pro-inflammatory mediators (СOX-2, HIF-1α, and IL-17) significantly increased and SP-D level decreased in BALF. Administration of celecoxib was accompanied by normalization of BALF cytology profile and decrease in COX-2, HIF-1α, and IL-17 levels in BALF; this could indicate a reduction in the hypoxic signaling activity and in inflammation. The growth of SP-D concentration could be considered as a result of the alveolar epithelium restoration. This was confirmed by histological examination of the lung tissue. Conclusion. COX-2 inhibition suppressed HIF-1α-signaling and decreased the lung inflammation. The results confirm a functional and regulatory relationship between HIF-1α and COX-2 signaling cascades that could be a therapeutic target for preventing the progression of inflammation and airway remodeling in COPD.

Sequential broncho-alveolar lavages reflect distinct pulmonary compartments: clinical and research implications in lung transplantation

BackgroundBronchoalveolar lavage (BAL) has proven to be very useful to monitor the lung allograft after transplantation. In addition to allowing detection of infections, multiple BAL analytes have been proposed as potential biomarkers of lung allograft rejection or dysfunction. However, BAL collection is not well standardized and differences in BAL collection represent an important source of variation. We hypothesized that there are systematic differences between sequential BALs that are relevant to BAL analysis.MethodsAs part of 126 consecutive bronchoscopies in lung transplant recipients, two sequential BALs (BAL1 and BAL2) were performed in one location during each bronchoscopy by instilling and suctioning 50 ml of normal saline twice into separate containers. Cell concentration, viability and differentials, Surfactant Protein-D (SP-D), Club Cell Secretory Protein (CCSP), and levels of CXCL10, IL-10, CCL2, CCL5, VEGF-C, RAGE, CXCL9, CXCL1, IL-17A, IL-21, PDGF, and GCSF were compared between BAL1 and BAL2.ResultsTotal cell concentration did not differ between BAL1 and BAL2; however, compared to BAL2, BAL1 had more dead cells, epithelial cells, neutrophils, and higher concentrations of airway epithelium-derived CCSP and inflammatory markers. BAL2 had a higher concentration of SP-D compared to BAL1.ConclusionIn this study performed in lung transplant recipients, we show that sequential BALs represent different lung compartments and have distinct compositions. BAL1 represents the airway compartment with more epithelial cells, neutrophils, and epithelium-derived CCSP. Conversely, BAL2 samples preferentially the distal bronchoalveolar space with greater cell viability and higher SP-D. Our findings illustrate how the method of BAL collection can influence analyte concentrations and further emphasize the need for a standardized approach in translational research involving BAL samples.

Serum concentrations of Krebs von den Lungen-6, surfactant protein D, and matrix metalloproteinase-2 as diagnostic biomarkers in patients with asbestosis and silicosis: a case\u2013control study

BackgroundAsbestosis and silicosis are progressive pneumoconioses characterized by interstitial fibrosis following exposure to asbestos or silica dust. We evaluated the potential diagnostic biomarkers for these diseases.MethodsThe serum concentrations of Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), and matrix metalloproteinase-2 (MMP-2), MMP-7, and MMP-9 were measured in 43 patients with asbestosis, 45 patients with silicosis, 40 dust-exposed workers (DEWs) without pneumoconiosis, and 45 healthy controls (HCs). Chest high-resolution computed tomography (HRCT) images were reviewed by experts blinded to the clinical data. According to the receiver operating characteristic (ROC) curve, the ideal level of each biomarker and its diagnostic sensitivity were obtained.ResultsThe serum KL-6 and MMP-2 concentrations were highest in patients with asbestosis, particularly in comparison with those in DEWs and HCs (P<0.05). The serum SP-D concentration was significantly higher in patients with asbestosis than in patients with silicosis, DEWs, and HCs (P<0.01), whereas no significant difference was noted among patients with silicosis, DEWs, and HCs. No significant difference in the serum MMP-7 or -9 concentration was found among patients with asbestosis, patients with silicosis, DEWs, or HCs. Among patients with asbestosis, the serum KL-6 concentration was significantly correlated with the lung fibrosis scores on HRCT and negatively correlated with the forced vital capacity (FVC) % predicted and diffusing capacity of the lung for carbon monoxide (DLCO) % predicted. The serum SP-D and MMP-2 concentrations were negatively correlated with the DLCO % predicted (all P<0.05). The order of diagnostic accuracy according to the ROC curve was KL-6, SP-D, and MMP-2 in patients with asbestosis alone and in the combination of both patients with asbestosis and those with silicosis. The combination of all three biomarkers may increase the possibility of diagnosing asbestosis (sensitivity, 93%; specificity, 57%) and both asbestosis and silicosis (sensitivity, 83%; specificity, 62%).ConclusionsKL-6, SP-D, and MMP-2 are available biomarkers for the adjuvant diagnosis of asbestosis and silicosis. The combination of all three biomarkers may improve the diagnostic sensitivity for asbestosis and silicosis.

Genetic variations of the bitter taste receptor TAS2R38 are associated with obesity and impact on single immune traits.

Changes in genetic variations affecting the taste receptor, type 2, member 38 (TAS2R38) may identify the interacting mechanism leading to obesity and potential associations with proteins partaking in innate immunity, such as surfactant protein D (SPD) and mannan-binding lectin (MBL). We evaluated haplotypes of the bitter-taste receptor TAS2R38 in an identification sample of 210 women in different weight conditions, including anorexia nervosa and obesity. The association with SPD and MBL was tested in an independent sample picturing general population (n = 534). The relationship with obesity was validated in an extended final sample of 1319 participants. In the sample comprised of women in extreme weight conditions, increased obesity was identified in AVI/AVI subjects (OR = 2.5 [1.06-6.11], p = 0.035). In the sample picturing general population, increased SPD and MBL concentrations were found in nonsmoking AVI carriers. In this cohort, smoking and obesity blunted associations between TAS2R38 haplotypes and SPD and MBL. In the extended sample, the association of AVI/AVI haplotypes with increased obesity was also identified (OR = 1.4 [0.99/1.85], p = 0.049), being more robust in subjects aged <40 years (OR = 1.9 [1.06/3.42], p = 0.031). Current data reinforce the impact of TAS2R38 gene on phenotypic and clinical outputs affecting obesity, showing significant associations with extreme weight conditions (i.e., obesity and anorexia nervosa), and changes in both olfactory capacity and immune traits.

Effect of controlled human exposure to diesel exhaust and allergen on airway surfactant protein D, myeloperoxidase and club (Clara) cell secretory protein 16.

Air pollution is a major cause of global morbidity and mortality. Air pollution and aeroallergens aggravate respiratory illness, but the variable effects of air pollutants and allergens in the lung are poorly understood. To determine the effects of diesel exhaust (DE) and bronchial allergen challenge as single and dual exposures on aspects of innate immunity in the airway as reflected by surfactant protein D (SPD), myeloperoxidase (MPO) and club (Clara) cell secretory protein 16 (CC16) in 18 atopic individuals. In this double-blind, randomized crossover study, atopic individuals were exposed to DE or filtered air, followed by endobronchial allergen or saline 1 hour after inhalational exposure. Bronchoalveolar lavage, bronchial washings, nasal lavage and blood samples were obtained 48 hours after exposures and assayed for CC16, MPO and SPD by ELISA. In bronchial samples, the concentration of SPD increased from 53.3 to 91.8 ng/mL after endobronchial allergen, with no additional contribution from DE. MPO also increased significantly in response to allergen (6.8 to 14.7 ng/mL), and there was a small additional contribution from exposure to DE. The concentration of CC16 decreased from 340.7 to 151.0 ng/mL in response to DE, with minor contribution from allergen. These changes were not reflected in nasal lavage fluid or plasma samples. These findings suggest that allergen and DE variably influence different aspects of the innate immune response of the lung. SPD and MPO, known markers of allergic inflammation in the lung, are strongly increased by allergen while DE has a minor effect therein. DE induces a loss of CC16, a protective protein, while allergen has a minor effect therein. Results support site- and exposure-specific responses in the human lung upon multiple exposures.

Club Cell-16 and RelB as Novel Determinants of Arterial Stiffness in Exacerbating COPD Patients.

BackgroundExacerbations of chronic obstructive pulmonary disease (COPD) are acute events of worsened respiratory symptoms that may increase the risk of cardiovascular disease (CVD), a leading cause of mortality amongst COPD patients. The utility of lung-specific inflammatory mediators such as club cell protein-16 (CC-16) and surfactant protein D (SPD) and that of a novel marker of CV outcomes in COPD- RelB- in predicting adverse cardiovascular events during exacerbation is not known.MethodsThirty-eight subjects with COPD admitted to the hospital for severe exacerbation were included in this analysis. Clinical, physiological and arterial stiffness measurements were performed within 72 hours of admission; this was followed by measurements taken every 3 days until hospital discharge, then once a week until 30 days after discharge, and then again at 90 and 180 days. Plasma concentrations of inflammatory mediators were measured from peripheral venous blood taken at admission, and at days 15, 30, 90 and 180.ResultsCC-16 and RelB concentrations were increased at day 15 of exacerbations whereas SPD concentrations were decreased. The course of change in CC-16 and RelB levels over time was inversely associated with that of carotid-femoral pulse wave velocity, the gold-standard measure of arterial stiffness. Increases in CC-16 could predict a decreased number of subsequent exacerbations during follow-up.ConclusionsLung-specific (CC-16) and novel (RelB) biomarkers are associated with systemic cardiovascular changes over time. CC-16 can predict subsequent exacerbations in subjects with severe COPD and may be an important biomarker of pulmonary and systemic stress in COPD.

Surfactant Protein-D Is Essential for Immunity to Helminth Infection.

Pulmonary epithelial cell responses can enhance type 2 immunity and contribute to control of nematode infections. An important epithelial product is the collectin Surfactant Protein D (SP-D). We found that SP-D concentrations increased in the lung following Nippostrongylus brasiliensis infection; this increase was dependent on key components of the type 2 immune response. We carried out loss and gain of function studies of SP-D to establish if SP-D was required for optimal immunity to the parasite. N. brasiliensis infection of SP-D-/- mice resulted in profound impairment of host innate immunity and ability to resolve infection. Raising pulmonary SP-D levels prior to infection enhanced parasite expulsion and type 2 immune responses, including increased numbers of IL-13 producing type 2 innate lymphoid cells (ILC2), elevated expression of markers of alternative activation by alveolar macrophages (alvM) and increased production of the type 2 cytokines IL-4 and IL-13. Adoptive transfer of alvM from SP-D-treated parasite infected mice into naïve recipients enhanced immunity to N. brasiliensis. Protection was associated with selective binding by the SP-D carbohydrate recognition domain (CRD) to L4 parasites to enhance their killing by alvM. These findings are the first demonstration that the collectin SP-D is an essential component of host innate immunity to helminths.