Surfactant Protein D Research Articles

Clinical significance of melatonin level in patients with chronic obstructive pulmonary disease

The objective of this study was to analyze an impact of melatonin on clinical course, cytokine profile and surfactant protein D level in patients with COPD. Methods. The study involved 88 patients (62 men and 26 women) with stable moderate-to-severe COPD (GOLD stages II – IV), the "frequent exacerbator" phenotype (group D), aged 40 to 80 years (mean age, 68.61 ± 0.72 years). The patients were divided into three groups according to COPD stage: 31 patients (22 men and 9 women; mean age, 67.42 ± 1.38 years) with COPD GOLD stage II); 29 patients (19 men and 10 women; mean age, 68.83 ± 1.21 years) with COPD GOLD stage III); and 28 patients (21 men and 7 women; mean age, 69.71 ± 1.09 years) with COPD GOLD stage IV. Clinical and laboratory parameters were assessed at baseline and in 1 year of the follow-up. Results. Severe COPD course with frequent exacerbations, prominent clinical signs and significant impact on quality of life was directly and statistically significantly related to lower melatonin level. This was also associated with different sleep disorders, high-grade chronic systemic inflammation, and lower surfactant protein D (SP-D) level. Conclusion. Lower melatonin level in COPD patients could cause sleep disorders, decrease the antioxidant defense and SP-D level, increase the pro-inflammatory activity and decrease the anti-inflammatory activity.

Evaluation of changes in the serum levels of Krebs von den Lungen-6 and surfactant protein-D over time as important biomarkers in idiopathic fibrotic nonspecific interstitial pneumonia.

Some cases of idiopathic fibrotic nonspecific interstitial pneumonia (f-NSIP) show a progressive course that is similar to that of idiopathic pulmonary fibrosis. However, it is difficult to predict poor patient outcomes. This study aimed to evaluate whether serial changes in serum levels of Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) can predict disease progression. We retrospectively analyzed the medical records of 75 patients with idiopathic f-NSIP. Disease behavior was categorized into two groups depending on long-term change of pulmonary function: progressive type (≥5%/year relative decline in the slope of forced vital capacity [FVC] and/or ≥7.5%/year relative decline in the slope of %diffusing capacity of the lung for carbon monoxide [%DLCO]) and stable type. Levels of KL-6 and SP-D and results of pulmonary function tests, which were performed parallelly, were reviewed and analyzed using a linear mixed-effects model. The study subjects comprised 62 patients with stable type and 13 patients with progressive type disease behavior. Among these subjects, 50 patients fulfilled the diagnostic criteria of interstitial pneumonia with autoimmune features (IPAF). Serum levels of both KL-6 and SP-D at baseline showed a negative correlation with %DLCO, but not with FVC, and these biomarkers were not related to disease progression. Persistently high levels of KL-6 and SP-D correlated with progressive type disease behavior in idiopathic (non-IPAF) f-NSIP. Changes in serum KL-6 and SP-D levels over time may provide useful predictive information on disease behavior during treatment in patients with idiopathic f-NSIP and especially in those with non-IPAF f-NSIP.

Endotoxin and Hydrogen Sulphide Exposure and Effects on the Airways Among Waste Water Workers in Sewage Treatment Plants and Sewer Net System.

The purpose of this study is to investigate whether airborne exposure to endotoxins, hydrogen sulphide (H2S), and inhalable particles negatively impacts the respiratory system and inflammatory blood proteins in sewage plant and sewer net system workers and, further, to determine dose-response associations between exposure and health outcomes. In total, 148 waste water workers (WWWs) from urban and rural sewage plants and the sewer net system participated. One hundred and twenty-one workers were exposed to sewage, 46 from sewage plants and 75 from the sewer net system. Twenty-seven workers were characterized as little or not exposed and served as an internal reference group. Personal inhalable samples were analysed for endotoxins (Limulus assay), particle dust (gravimetrically) and Salmonella and Yersinia spp. (polymerase chain reaction method, PCR). Levels of H2S were measured using personal electro chemical sensors. Intercellular adhesion molecule 1 (ICAM-1), interleukin 8 (IL-8), surfactant protein D (SP-D), club cell protein 16 (CC16), and macrophage inflammatory protein (MIP) were determined by enzyme-linked immunosorbent assay and C-reactive protein (CRP) by an HS-MicroCRP assay in blood samples. Workers in sewage plants were exposed to significantly higher levels of endotoxins compared to workers in the sewer net system [median 55 EU m-3 (4-262 EU m-3) and median 27 EU m-3 (1-304 EU m-3), respectively]. The estimated H2S index showed higher values when working in the sewer net system [median 3.1 (0.5-78.1)] compared to workers at the sewage plants [median 1.3 (0.5-9.3)], and the most excessive exposure was collecting sewage from cesspools (273 p.p.m.). No viable airborne Salmonella and Yersinia spp. were detected. The exposed workers had significantly higher CRP compared to the referents [1.2 µg ml-1 (0.1-19.0 µg ml-1) and 0.8 µg ml-1 (0.1-5.0 µg ml-1), respectively] and lower forced expiratory volume in 1 s (FEV1)% [92.6%, standard deviation (SD) 14.6 and 102.0%, SD 10.1, respectively], with numbers given as mean and SD. The serum concentration of CRP was significantly and negatively associated with FEV1% (β = -7.7, R2 = 0.05) and forced vital capacity % (β = -8.5, R2 = 0.08), and the serum concentration of ICAM-1 with the estimated exposure to H2S (β = -19.9, R2 = 0.07). Despite moderate levels of endotoxin and H2S exposure, the results indicate an impact of these agents on lung function and the adhesion molecule ICAM-1, and a low-grade systemic inflammation was indicated in increased levels of CRP.

The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation.

Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.

Progress in surfactant protein D-involved immune inflammatory responses

Surfactant protein D (SP-D) is an important component of the surfactant family and expressed in lung as well as many other organs. SP-D is a natural immune protein, which plays an important role in immune defense in lung tissues and in the regulation of inflammatory responses. Moreover, it also participates in immune inflammatory responses in other organs. This paper reviewed the function of SP-D in the regulation of immune inflammatory responses and its regulatory mechanisms in common diseases, and summarized the prospect of SP-D in disease treatment. Key words: Surfactant protein D; Infection; Immune inflammation; Regulatory mechanism

The Lung Mucosa Environment in the Elderly Increases Host Susceptibility to Mycobacterium tuberculosis Infection.

As we age, there is an increased risk for the development of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection. Few studies consider that age-associated changes in the alveolar lining fluid (ALF) may increase susceptibility by altering soluble mediators of innate immunity. We assessed the impact of adult or elderly human ALF during Mtb infection in vitro and in vivo. We identified amplification of pro-oxidative and proinflammatory pathways in elderly ALF and decreased binding capability of surfactant-associated surfactant protein A (SP-A) and surfactant protein D (SP-D) to Mtb. Human macrophages infected with elderly ALF-exposed Mtb had reduced control and fewer phagosome-lysosome fusion events, which was reversed when elderly ALF was replenished with functional SP-A/SP-D. In vivo, exposure to elderly ALF exacerbated Mtb infection in young mice. Our studies demonstrate how the pulmonary environment changes as we age and suggest that Mtb may benefit from declining host defenses in the lung mucosa of the elderly.

Surfactant Protein D Reverses the Gene Signature of Transepithelial HIV-1 Passage and Restricts the Viral Transfer Across the Vaginal Barrier.

Effective prophylactic strategy against the current epidemic of sexually transmitted HIV-1 infection requires understanding of the innate gatekeeping mechanisms at the genital mucosa. Surfactant protein D (SP-D), a member of the collectin family of proteins naturally present in the vaginal tract, is a potential HIV-1 entry inhibitor at the cellular level. Human EpiVaginal tissues compartmentalized in culture inserts were apically exposed to HIV-1 and/or a recombinant fragment of human SP-D (rfhSP-D) and viral passage was assessed in the basal chamber containing mononuclear leukocytes. To map the gene signature facilitating or resisting the transepithelial viral transfer, microarray analysis of the HIV-1 challenged EpiVaginal tissues was performed in the absence or presence of rfhSP-D. Mucosal biocompatibility of rfhSP-D was assessed ex vivo and in the standard rabbit vaginal irritation model. The passage of virus through the EpiVaginal tissues toward the underlying target cells was associated with a global epithelial gene signature including differential regulation of genes primarily involved in inflammation, tight junctions and cytoskeletal framework. RfhSP-D significantly inhibited HIV-1 transfer across the vaginal tissues and was associated with a significant reversal of virus induced epithelial gene signature. Pro-inflammatory NF-κB and mTOR transcripts were significantly downregulated, while expression of the tight junctions and cytoskeletal genes was upheld. In the absence of virus, rfhSP-D directly interacted with the EpiVaginal tissues and upregulated expression of genes related to structural stability of the cell and epithelial integrity. There was no increment in the viral acquisition by the PBMCs present in basal chambers wherein, the EpiVaginal tissues in apical chambers were treated with rfhSP-D. The effective concentrations of rfhSP-D had no effect on lactobacilli, epithelial barrier integrity and were safe on repeated applications onto the rabbit vaginal mucosa. This pre-clinical safety data, coupled with its efficacy of restricting viral passage via reversal of virus-induced gene expression of the vaginal barrier, make a strong argument for clinical trials of rfhSP-D as a topical anti-HIV microbicide.

Effect of dynamic lung compliance-guided PEEP titration on lung injury in elderly patients undergoing robot-assisted radical prostatectomy

Objective To evaluate the effect of dynamic lung compliance(Cydn)-guided positive end-expiratory pressure(PEEP)titration on lung injury in the patients undergoing robot-assisted radical prostatectomy. Methods Forty American Society of Anesthesiologists physical status Ⅱ or Ⅲ patients, aged 65-80 yr, with body mass index of 19-28 kg/m2, scheduled for elective robot-assisted radical prostatectomy under general anesthesia, were divided into 2 groups(n=20 each)using a random number table method: control group(group C)and PEEP group(group P). Mechanical ventilation was performed according to preset parameters after tracheal intubation in group C, and PEEP was set by a double titration method after tracheal intubation and after pneumoperitoneum in group P. At 4 min after intubation(T1), 4 min, 1 h and 2 h after establishing pneumoperitoneum-Trendelenburg position(T2-4), and 1 and 30 min after extubation(T5, 6)in group C or at 4 min after completing the first PEEP titration(T1), 4 min, 1 h and 2 h after completing the second PEEP titration(T2-4)and T5, 6 in group P, blood samples were collected from the radial artery for determination of club cell protein 16, surfactant protein-D, tumor necrosis factor-alpha and interleukin-6 concentrations in serum(by enzyme-linked immunosorbent assay). Results Compared with group C, the serum concentrations of club cell protein 16 at T2-6 and surfactant protein-D, tumor necrosis factor-alpha and interleukin-6 at T3-6 were significantly decreased in group P(P<0.05). Conclusion Cydn-guided PEEP titration can reduce the lung injury in patients undergoing robot-assisted radical prostatectomy. Key words: Lung compliance; Positive-pressure respiration; Prostatic neoplasms; Respiratory function tests

Naftopidil reduced the proliferation of lung fibroblasts and bleomycin-induced lung fibrosis in mice.

Naftopidil, an α‐1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α‐1 adrenoceptor inhibitor. We examined the incorporation of 5‐bromo‐2ʹ‐deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme‐linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound‐healing assay, and mRNA expressions of type IV collagen and α‐smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin‐induced lung fibrosis in mice were evaluated using histology, micro‐computed tomography, and surfactant protein‐D levels in serum. Naftopidil, dose‐dependently but independently of phenoxybenzamine, inhibited 5‐bromo‐2ʹ‐deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α‐smooth muscle actin in one normal lung fibroblast line. Histological and micro‐computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein‐D levels in bleomycin‐induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis.

Bronchoalveolar fluid and plasma inflammatory biomarkers in contemporary ARDS patients

Purpose: Bronchoalveolar fluid (BALF) and plasma biomarkers are often endpoints in early phase randomized trials (RCTs) in acute respiratory distress syndrome (ARDS). With ARDS mortality decreasing, we analyzed baseline biomarkers in samples from contemporary ARDS patients participating in a prior RCT and compared these to historical controls.Materials and methods: Ninety ARDS adult patients enrolled in the parent trial. BALF and blood were collected at baseline, day 4 ± 1, and day 8 ± 1. Interleukins-8/-6/-1β/-1 receptor antagonist/-10; granulocyte colony stimulating factor; monocyte chemotactic protein-1; tumour necrosis factor-α; surfactant protein-D; von Willebrand factor; leukotriene B4; receptor for advanced glycosylation end products; soluble Fas ligand; and neutrophil counts were measured.Results: Compared to historical measurements, our values were generally substantially lower, despite our participants being similar to historical controls. For example, our BALF IL-8 and plasma IL-6 were notably lower than in a 1999 RCT of low tidal volume ventilation and a 2007 biomarker study, respectively.Conclusions: Baseline biomarker levels in current ARDS patients are substantially lower than 6–20 years before collection of these samples. These findings, whether from ICU care changes resulting in less inflammation or from variation in assay techniques over time, have important implications for design of future RCTs with biomarkers as endpoints.

Effects of electroacupuncture on postoperative acute lung injury in patients with acute abdomen complicated with abdominal infection

Objective To evaluate the effects of electroacupuncture(EA) on postoperative acute lung injury(ALI) in patients with acute abdomen complicated with abdominal infection. Methods Ninety patients of both sexes with acute abdomen complicated with abdominal infection, with body mass index of 18-30 kg/m2, aged 35-64 yr, of American Society of Anesthesiologists physical status Ⅰor Ⅱ, scheduled for elective abdominal surgery with general anesthesia, were divided into 3 groups(n=30 each) using a random number table method: control group(group C), EA at acupoint group(group E) and EA at non-acupoint group(group N). Anesthesia was induced with midazolam, propofol, cis-atracurium and sufentanil.The patients were mechanically ventilated after tracheal intubation.Anesthesia was maintained with inhalation of sevoflurane, IV infusion of propofol and cis-atracurium and intermittent IV boluses of sufentanil.At 15 min of anesthesia induction, 2 h after skin incision and 2, 12 and 24 h after tracheal intubation, Hegu, Zusanli and Neiguan acupoints were stimulated for 15 min every time in group E, and the points 1 cm lateral to the acupoints of Hegu, Zusanli and Neiguan were stimulated for 15 min every time in group N, with disperse-dense waves, frequency 2/15 Hz, wave length 0.2-0.6 ms, at a voltage of 1-2 mA.Arterial blood samples were collected at 15 min before induction(T1) and 24 and 48 h after operation(T2 and T3) for blood gas analysis, oxygenation index was calculated, and the development of ALI(oxygenation index<300 mmHg) was recorded at T2 and T3.The concentrations of club cell protein 16(CC16), surfactant protein D(SP-D), soluble receptor for advanced glycation end products(sRAGE), interleukin-1(IL-1), IL-10, and tumor necrosis factor-alpha(TNF-α) in serum were detected by enzyme-linked immunosorbent assay. Results Compared with the baseline at T1, the serum concentrations of CC16, SP-D, sRAGE, IL-1 and TNF-α were significantly increased, and the serum IL-10 concentrations were decreased at T2 in C, E and N groups(P 0.05). Conclusion Although EA does not decrease the occurrence of ALI, it mitigates the degree of ALI to some extent in the patients with acute abdomen complicated with abdominal infection. Key words: Elactroacupuncture; Abdomen, acute; Intraabdominal infections; Respiratory distress syndrome, adult

Colonic Epithelial Surfactant Protein D Expression Correlates with Inflammation in Clinical Colonic Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract. Surfactant protein D (SP-D) is expressed in the intestinal epithelium and is essential for innate host defense and regulation of inflammatory responses. Genetic variations of SP-D are associated with IBD, but the effects of SP-D in clinical disease development have not been clarified. We hypothesized that colonic epithelial SP-D expression is increased in parallel with intestinal inflammation with the capacity to dampen deleterious effects. Surgical specimens from IBD patients including Crohn's disease (n = 9) and ulcerative colitis (n = 18) were scored for expression of SP-D and inflammatory activity. Cohoused Sftpd+/+ and Sftpd-/- mouse littermates were subjected to dextran sodium sulfate (DSS) for 7 days to induce colitis. Colonic tissue was scored for histologic damage and analyzed for inflammatory markers and expression of SP-D. Surgical specimens from IBD patients showed a strong positive correlation between immunoscore for SP-D and inflammatory activity (R2 = 0.78, P < 0.0001). In mice, colonic epithelial SP-D expression was very low, and DSS-induced colitis was unaffected by SP-D deficiency, although DSS induced transcription of colonic SP-D to a mild degree. A strong positive correlation between inflammatory activity and epithelial expression of SP-D was observed in surgical specimens from IBD patients supporting a role for SP-D in clinical disease. The in vivo study was inconclusive due to very low intestinal SP-D expression in the mouse. Further studies are warranted to support that increased SP-D expression in the human colonic epithelium is protective against intestinal inflammation.

Complement Dependent and Independent Interaction Between Bovine Conglutinin and Mycobacterium bovis BCG: Implications in Bovine Tuberculosis.

Bovine conglutinin, the first animal collectin to be discovered, is structurally very similar to Surfactant Protein D (SP-D). SP-D is known to interact with Mycobacterium tuberculosis, and the closely-related M. bovis, the causative agent of bovine tuberculosis. We speculated that due to the overall similarities between conglutinin and SP-D, conglutinin is likely to have a protective influence in bovine tuberculosis. We set out to investigate the role of conglutinin in host-pathogen interaction during mycobacterial infection. We show here that a recombinant truncated form of conglutinin (rfBC), composed of the neck and C-type lectin domains, binds specifically and in a dose-dependent manner to the model organism Mycobacterium bovis BCG. rfBC showed a significant direct bacteriostatic effect on the growth of M. bovis BCG in culture. In addition, rfBC inhibited the uptake of M. bovis BCG by THP-1 macrophages (human monocyte lineage cell line) and suppressed the subsequent pro-inflammatory response. Conglutinin is well-known as a binder of the complement activation product, iC3b. rfBC was also able to inhibit the uptake of complement-coated M. bovis BCG by THP-1 macrophages, whilst modulating the pro-inflammatory response. It is likely that rfBC inhibits the phagocytosis of mycobacteria by two distinct mechanisms: firstly, rfBC interferes with mannose receptor-mediated uptake by masking lipoarabinomannan (LAM) on the mycobacterial surface. Secondly, since conglutinin binds iC3b, it can interfere with complement receptor-mediated uptake via CR3 and CR4, by masking interactions with iC3b deposited on the mycobacterial surface. rfBC was also able to modulate the downstream pro-inflammatory response in THP-1 cells, which is important for mobilizing the adaptive immune response, facilitating containment of mycobacterial infection. In conclusion, we show that conglutinin possesses complement-dependent and complement-independent anti-mycobacterial activities, interfering with both known mechanisms of mycobacterial uptake by macrophages. As mycobacteria are specialized intracellular pathogens, conglutinin may inhibit M. bovis and M. tuberculosis from establishing an intracellular niche within macrophages, and thus, negatively affect the long-term survival of the pathogen in the host.

Surfactant Protein D (SP-D) Inhibits Neutrophil Extracellular DNA Trap Formation: Effects of S-nitrosylation

Surfactant Protein D (SP-D) Inhibits Neutrophil Extracellular DNA Trap Formation: Effects of S-nitrosylation

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.

Surfactant protein D as a marker for pulmonary complications in pediatric patients with sickle cell disease: Relation to lung function tests.

Surfactant protein D (SP-D) is considered a candidate biomarker for lung integrity and for disease progression. We determined the level of SP-D in children and adolescents with SCD and assessed its possible relation to pulmonary complications and lung function. Serum SP-D levels were assessed in 50 SCD patients compared with 30 healthy controls. High-resolution computerized tomography (HRCT) of the chest was done. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1 ), FEV1 /FVC% and forced expiratory flow rate during 25-75% of expiration (FEF25-75%) were determined. SP-D was significantly higher in SCD patients than controls, particularly patients with sickle cell anemia than those with sickle β-thalassemia. SP-D levels were significantly associated with increasing severity of interstitial lung disease. The highest SP-D levels were observed among patients with restrictive lung disease followed by mixed type then obstructive lung disease. SP-D was positively correlated to HbS and serum ferritin while negatively correlated to duration of hydroxyurea treatment and parameters of pulmonary functions. ROC curve analysis revealed that SP-D cutoff value 720 ng/mL could significantly detect the presence of abnormal pulmonary function among SCD patients with 82% sensitivity and 88% specificity. Logistic regression analysis showed that SP-D is an independent factor related to abnormal pulmonary function in SCD. SP-D may be a promising biomarker for screening of SCD patients for risk of later pulmonary complications.

Increased surfactant protein-D levels in the airways of preterm neonates with sepsis indicated responses to infectious challenges.

AimSepsis is multifactorial and potentially devastating for preterm neonates. Changes in surfactant protein‐D (SP‐D), phosphatidylcholine (PC) and PC molecular species during infection may indicate innate immunity or inflammation during sepsis. We aimed to compare these important pulmonary molecules in ventilated neonates without or with sepsis.MethodsEndotracheal aspirates were collected from preterm neonates born at 23–35 weeks and admitted to the neonatal intensive care unit at the John Radcliffe Hospital, Oxford, UK, from October 2000 to March 2002. Samples were collected at one day to 30 days and analysed for SP‐D, total PC and PC molecular species concentrations using enzyme‐linked immunosorbent assay and mass spectrometry.ResultsWe found that 8/54 (14.8%) neonates developed sepsis. SP‐D (p < 0.0001), mono‐ and di‐unsaturated PC were significantly increased (p = 0.05), and polyunsaturated PC was significantly decreased (p < 0.01) during sepsis compared to controls. SP‐D:PC ratios were significantly increased during sepsis (p < 0.001), and SP‐D concentrations were directly related to gestational age in neonates with sepsis (r2 = 0.389, p < 0.01).ConclusionIncreased SP‐D levels and changes in PC molecular species during sepsis were consistent with direct or indirect pulmonary inflammatory processes. Very preterm neonates we able to mount an acute inflammatory innate immune response to infectious challenges, despite low levels of surfactant proteins at birth.

Indium Lung: Discovery, Pathophysiology and Prevention.

Indium is mainly used as indium-tin oxide (ITO), which has a unique character of transparency, and is a requisite in making liquid crystal displays. Pulmonary toxicity of indium compounds in humans were not recognized until the last 2 decades. Several initial human cases of indium-related lung disease, named indium lung, were reported in Japan, with their main pathologic findings being interstitial pneumonia, emphysema and cholesterol crystals-containing granulomas. In 2010, three cases with alveolar proteinosis were reported from the United States and China. As of March 2019, more than 10 cases of interstitial pneumonia-dominant indium lung have been reported. Cross-sectional studies in indium workers indicate that the serum indium concentration (sIn) is closely related to the exposure period, the extent of interstitial as well as emphysematous changes of the lung on high-resolution computed tomography (HRCT) and serum biomarkers of interstitial pneumonia, including KL-6 and surfactant protein-D (SP-D). Longitudinal studies have shown it is possible to reduce the sIn as well as the interstitial shadows on HRCT; however, emphysematous lesions increased progressively in heavily exposed workers, even after cessation of exposure. Early detection is required to prevent irreversible changes. The first case of lung cancer associated with indium lung developed in a nonsmoking ex-worker. He had been diagnosed with indium lung and stopped working in indium processing 17 years before. This suggested there is a need for appropriate screening to detect for complications of lung cancer at early stages for those with indium lung.

Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis.

Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defense in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation. Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype, and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated. Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro. Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation.

Antifungal activities of surfactant protein D in an environment closely mimicking the lung lining

At the lung lining innate defenses protect our lungs against inhaled fungal cells that could pose a threat to our health. These defenses are comprised of mucociliary clearance, soluble effector molecules and roaming phagocytic cells, such as macrophages and neutrophils. How important each of these defenses is during fungal clearance depends on the specific fungal pathogen in question and on the stage of infection. In this study the localization and antifungal activity of the lung surfactant protein D (SP-D) was studied in an environment mimicking the lung lining. To this end Calu-3 cells were grown on an air-liquid interface allowing them to polarize and to produce mucus at their apical surface. Additionally, neutrophils were added to study their role in fungal clearance. Two fungal pathogens were used for these experiments: Candida albicans and Aspergillus fumigatus, both of clinical relevance. During fungal infection SP-D localized strongly to both fungal surfaces and stayed bound through the different stages of infection. Furthermore, SP-D decreased fungal adhesion to the epithelium and increased fungal clearance by neutrophils from the epithelial surface. These findings suggest that SP-D plays an important role at the different stages of pulmonary defense against fungal intruders.