BACKGROUND: Surfactant protein D (SP-D) is a critical component of the innate immune system intrinsically linked to energy metabolism. However, the relationship of SP-D gene polymorphisms and gestational diabetes mellitus (GDM) remains unclear. In this study, we analyzed SP-D gene polymorphisms in GDM patients and nondiabetic controls and then determined the association of SP-D gene polymorphisms with GDM.
METHODS: We examined a common genetic polymorphism located in the SP-D coding region (rs721917, Met31Thr) in GDM patients (n = 147) and healthy pregnant controls (n = 97) by using a cleaved amplification polymorphism sequence-tagged sites (PCR-RFLP) technique. The level of SP-D protein in the serum of GDM patients and nondiabetic controls was determined by ELISA. The gene and allele frequencies of SP-D and their association with GDM as well as SP-D protein levels were analyzed and expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs).
RESULTS: We found that there was a significant association of the SP-D polymorphism (rs721917) with GDM. The SP-D (T/T) genotype was found in 11.6% and 21.6% of GDM patients and matched healthy controls, respectively (odds ratio, 0.473; 95% confidence interval, 0.235-0.952; P = 0.033), indicating that women with the (T/T) genotype had a lower prevalence of GDM (OR = 0.473). Women with the T/C genotype showed an increased risk of GDM (odds ratio, 2.440; 95% confidence interval, 1.162-5.123; P = 0.017). We did not observe corrections between glucose homeostasis markers and SP-D genotypes in women with GDM. Furthermore, serum SP-D levels were higher in GDM patients than in matched healthy controls.
CONCLUSIONS: This study found the first evidence that an SP-D gene polymorphism (rs721917) was associated with GDM, which may provide the basis for further study on how SP-D plays a regulatory role in GDM.

BACKGROUND: ALOX5, IL6R and SFTPD are all immune related genes that may be involved in the development of lung cancer. We sought to explore the effect of polymorphisms of these genes on the risk of lung cancer.
METHODS: Six single nucleotide polymorphisms (SNPs) were genotyped using a MassARRAY platform in a case-control cohort including 550 patients with lung cancer and 550 healthy controls.
RESULTS: The rs4845626-T and rs4329505-C alleles were associated with a decreased risk of lung cancer (p < 0.001), while the rs745986-G and rs2245121-A alleles were correlated with an increased risk of lung cancer (p < 0.01). The rs4845626-GT/GG and rs4329505-TC genotypes were protective against lung cancer (p < 0.001). However, the rs745986-AG and rs2245121-AG/AA genotypes were associated with an increased risk of lung cancer (p < 0.01). Stratification analysis showed that the rs4845626 and rs4329505 polymorphisms of IL6R were associated with a reduced risk of lung cancer in both smokers and nonsmokers (p < 0.05). However, rs892690, rs745986 and rs2115819 of ALOX5 were associated with an increased risk of disease in nonsmokers, while rs2245121 of SFTPD was correlated with a higher risk of disease in smokers (p < 0.05).
CONCLUSIONS: Our results provide candidate SNPs for early screening for lung cancer and new clues for further study of the pathogenesis of the disease.

BACKGROUND: Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of tuberous sclerosis complex (TSC). Because of its rarity, no previous study has described the detailed clinical course of this disease.
OBJECTIVE: This study aimed to clarify the longitudinal clinical characteristics of subjects with MMPH.
METHODS: Nine patients with MMPH diagnosed at Hokkaido University Hospital were retrospectively analyzed. Changes in computed tomography findings and pulmonary function were compared during the follow-up period. Serum levels of KL-6, surfactant protein (SP)-A, and SP-D were measured to clarify their potentials as blood biomarkers of the disease. Fourteen cases of lymphangiomyomatosis (LAM) were also included to compare their clinical characteristics with those of subjects with MMPH.
RESULTS: Of the 9 patients, 7 were female and 2 were male. The median age at diagnosis was 43 years (range, 19-56), and all cases were diagnosed following incidental abnormal radiographic findings. During the follow-up, 1 patient died of lung cancer, but others were radiographically stable and had stable pulmonary function. Serum levels of SP-A in 5 patients (mean, 146.4 ng/mL) and SP-D in 6 patients (mean, 337.3 ng/mL) were elevated in subjects with MMPH, whereas KL-6 levels were within the reference range (mean, 230 U/mL) in all patients. Levels of SP-A and SP-D were significantly higher in subjects with MMPH than those with LAM (p < 0.05).
CONCLUSIONS: Radiographic findings and pulmonary function were stable in all cases of MMPH. Serum SP-A and SP-D, but not KL-6, may be useful markers for suspicion of the presence of MMPH in patients with TSC.

BACKGROUND: Asbestosis 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.
METHODS: The 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.
RESULTS: The 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%).
CONCLUSIONS: KL-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.

Interstitial lung diseases induced by anticancer agents (ILD-AA) are rare adverse effects of anticancer therapy. However, prognostic biomarkers for ILD-AA have not been identified in patients with advanced lung cancer. Our aim was to analyze the association between serum biomarkers sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), and clinical characteristics in patients diagnosed with ILD-AA.
Between April 2011 and March 2016, 1224 advanced lung cancer patients received cytotoxic agents and epidermal growth factor receptor tyrosine kinase inhibitors at Juntendo University Hospital and Juntendo University Urayasu Hospital. Of these patients, those diagnosed with ILD-AA were enrolled in this case control study. ΔKL-6 and ΔSP-D were defined as the difference between the levels at the onset of ILD-AA and their respective levels prior to development of ILD-AA. We evaluated KL-6 and SP-D at the onset of ILD-AA, ΔKL-6 and ΔSP-D, the risk factors for death related to ILD-AA, the chest high resolution computed tomography (HRCT) findings, and survival time in patients diagnosed with ILD-AA.
Thirty-six patients diagnosed with ILD-AA were enrolled in this study. Among them, 14 patients died of ILD-AA. ΔSP-D in the patients who died was significantly higher than that in the patients who survived. However, ΔKL-6 did not differ significantly between the two groups. Moreover, ΔSP-D in patients who exhibited diffuse alveolar damage was significantly higher than that in the other patterns on HRCT. Receiver operating characteristic curve analysis was used to set the optimal cut off value for ΔSP-D at 398 ng/mL. Survival time for patients with high ΔSP-D (≥ 398 ng/mL) was significantly shorter than that for patients with low ΔSP-D. Multivariate analysis revealed that ΔSP-D was a significant prognostic factor of ILD-AA.
This is the first research to evaluate high ΔSP-D (≥ 398 ng/mL) in patients with ILD-AA and to determine the risk factors for ILD-AA in advanced lung cancer patients. ΔSP-D might be a serum prognostic biomarker of ILD-AA. Clinicians should evaluate serum SP-D during chemotherapy and should carefully monitor the clinical course in patients with high ΔSP-D.

OBJECTIVE: To determine the incidence of pneumonia and associated factors in a single-center systemic lupus erythematosus (SLE) cohort.
METHODS: We included all our SLE patients [1997 American College of Rheumatology (ACR) criteria] with ≥ 1 pneumonia event, and 196 age and sex-matched SLE controls with no pneumonia events. Cumulative clinical data, weighted Systemic Lupus International Collaborating Clinics/ACR damage index (wSLICC/ACR-DI), comorbidities, and risk factors for pneumonia were retrospectively collected. The standardized incidence ratio (SIR) of pneumonia was estimated. Polymorphisms at genes coding for mannose binding lectin (MBL), MBL-associated serine protease 2, Fc-gamma receptors, and surfactant proteins A1, A2, and D were determined, and their potential association with pneumonia was analyzed. Patients with and without pneumonia were compared using a multivariate logistic regression model for adjustment of pneumonia-associated factors.
RESULTS: Thirty-six of 232 patients with SLE had experienced ≥ 1 pneumonia event. SIR for pneumonia was 5.1 (95% CI 3.5-7.4; p < 0.0001). Excluding patients receiving immunosuppressive therapy at the time of pneumonia (13%), associations were found for Katz Severity Index (KSI) (p = 0.016), wSLICC/ACR-DI (p = 0.044), number of SLE criteria (p = 0.005), hospital admissions (p < 0.001), FCGR2A HH genotype (p = 0.03), previous use of immunosuppressive therapy (p = 0.049), cutaneous ulcers (p < 0.001), and vasculitis (p = 0.008) in bivariate analyses. In the multivariate analysis adjusted to previous immunosuppressive treatment, only KSI and FCGR2A HH genotype remained statistically significant (p = 0.05 and p = 0.03, respectively).
CONCLUSIONS: The incidence of pneumonia in patients with SLE is higher than that in the general population, and particularly high in severe SLE, regardless of immunosuppressive therapy. The HH genetic variant of FCGR2A appears to predispose patients with SLE to pneumonia.

OBJECTIVE: To investigate whether the Th1/Th2 balance and expressions of surfactant-associated proteins and cytokines in serum and bronchoalveolar lavage fluid (BALF) are associated with the development of coal workers\' pneumoconiosis (CWP).
METHODS: A case-control study was conducted among 72 CWP cases and 68 controls. Th1 and Th2 populations were measured by flow cytometry. Expressions of surfactant-associated proteins A and D (SPA and SPD) and cytokines in serum and BALF were detected by enzyme-linked-immunosorbent serologic assay. Data were analyzed by t test and logistic regression.
RESULTS: Higher Th2 and lower Th1/Th2 were observed in CWP (P < 0.05). Increased CWP risk was associated with elevated BALF-interleukin-10 (odds ratio [OR]: 25.97; 95% confidence interval [CI]: 2.17 to 49.77), serum-SPA/BALF-SPA (OR: 12.87; 95% CI: 1.11 to 148.72), and serum-SPD/BALF-SPD (OR: 77.91; 95% CI: 5.64 to 161.46), decreased BALF-SPA (OR: 0.06; 95% CI: 0.01 to 0.31) and BALF-SPD (OR: 0.07; 95% CI: 0.02 to 0.36).
CONCLUSIONS: The development of CWP might be associated with Th1/Th2 imbalance and increased BALF-interleukin-10, serum-SPA/BALF-SPA, and serum-SPD/BALF-SPD.

BACKGROUND: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist.
METHODS: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1∶1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls.
RESULTS: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm(3). Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively).
CONCLUSIONS: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

BACKGROUND: Surfactant protein D (SP-D) is a promising blood biomarker in patients with chronic obstructive pulmonary disease (COPD). Nevertheless, circulating levels of SP-D are not related to pulmonary functions. In the present exploratory study, we created a simple index of plasma to bronchoalveolar lavage (BAL) fluid ratio of SP-D (pSP-D/bSP-D), and determined whether this index would relate to the severity of airflow limitation and hence represent a superior biomarker than pSP-D alone.
METHODS: In 50 ex and current smokers (mean age 57.6±7.8 years, 74% men), SP-D was measured in BAL fluid and plasma samples, and the relationships between spirometric variables and a composite parameter - the pSP-D/bSP-D ratio were determined.
RESULTS: There was a significant inverse correlation between the pSP-D/bSP-D ratio and the severity of airflow obstruction, as measured by FEV1/FVC (p=0.012). In contrast, no relationship was observed between FEV1/FVC and pSP-D alone.
CONCLUSIONS: We suggest that integrating both lung and plasma expression of pneumo-proteins may be more useful than plasma expression alone in developing pneumo-proteins as potential biomarkers in COPD.

OBJECTIVE: The present review is aimed to introduce an new occupational lung disease, Indium Lung.
METHODS: We searched case reports and epidemiological studies concerning indium-related lung diseases and reviewed.
RESULTS: Up to March, 2010, 7 cases of interstitial pneumonia in Japanese indium-exposed workers, two cases of pulmonary alveolar proteinosis (PAP) in US indium-exposed workers, one case of PAP in a Chinese indium-exposed worker, and 4 cross-sectional surveys in Japan had been published. All cases and epidemiological studies in Japan indicate that exposure to hardly soluble indium compounds causes interstitial as well as emphysematous lung damages, which we call \"Indium Lung\". Based on the epidemiological studies, the Japan Society for Occupational Health proposed 3 μg/l of indium in serum as an occupational exposure limit based on biological monitoring to prevent significant increase of KL-6.
CONCLUSIONS: Long-term follow-up of currently and formerly indium-exposed workers is essential not only to clarify the natural history of indium lung but also to trace the incidence of lung cancer. It is also necessary to elucidate the mechanism of indium lung and difference in clinical manifestations between Japanese and US cases.