Diabetic nephropathy (DN) is currently the most common complication of diabetes. It is considered to be one of the leading causes of end-stage renal disease (ESRD) and affects many diabetic patients. The pathogenesis of DN is extremely complex and has not yet been clarified; however, in recent years, increasing evidence has shown the important role of innate immunity in DN pathogenesis. Pattern recognition receptors (PRRs) are important components of the innate immune system and have a significant impact on the occurrence and development of DN. In this review, we classify PRRs into secretory, endocytic, and signal transduction PRRs according to the relationship between the PRRs and subcellular compartments. PRRs can recognize related pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), thus triggering a series of inflammatory responses, promoting renal fibrosis, and finally causing renal impairment. In this review, we describe the proposed role of each type of PRRs in the development and progression of DN.
Alarmins/physiology* ; C-Reactive Protein/physiology* ; Diabetic Nephropathies/etiology* ; Endocytosis ; Humans ; Immunity, Innate ; Mannose-Binding Lectin/physiology* ; Pathogen-Associated Molecular Pattern Molecules ; Receptors, Pattern Recognition/physiology* ; Serum Amyloid P-Component/physiology* ; Signal Transduction

BACKGROUND/AIMS: Several studies have identified a role for nuclear factor erythroid 2-related factor 2 (Nrf2) in the development of chronic obstructive pulmonary disease (COPD). However, the relationship between the plasma Nrf2 level and the extent of systemic inflammation associated with COPD status remains unclear. METHODS: Patients diagnosed with COPD were recruited from St. Paul’s Hospital, The Catholic University of Korea, between July 2009 and May 2012. Patients were classified into two groups according to the severity of their symptoms on initial presentation, a COPD-stable group (n = 25) and a COPD-exacerbation group (n = 30). Seventeen patients were enrolled as a control group (n = 17). The plasma levels of Nrf2 and other systemic inf lammatory biomarkers, including interleukin 6 (IL-6), surfactant protein D (SP-D), and C-reactive protein (CRP), were measured. We collected clinical data including pulmonary function test results, and analyzed the relationships between the biomarker levels and the clinical parameters. RESULTS: Plasma Nrf2 and CRP levels significantly increased in a stepwise manner with an increase in inflammatory status (control vs. COPD-stable vs. COPD-exacerbation) (p = 0.002, p < 0.001). Other biomarkers of systemic inflammation (IL-6, SP-D) exhibited similar tendencies, but significant differences were not apparent. Furthermore, we observed negative correlations between the plasma level of Nrf2 and both the forced expiratory volume in 1 second (FEV1) (r = –0.339, p = 0.015) and the forced expiratory ratio (FEV1/forced vital capacity [FVC]) (r = –0.342, p = 0.014). However, CRP level was not correlated with any measured parameter. CONCLUSIONS: Plasma Nrf2 levels gradually increased in line with disease severity and the extent of systemic inflammation in patients with COPD.
Biomarkers ; C-Reactive Protein ; Forced Expiratory Volume ; Humans ; Inflammation ; Interleukin-6 ; Korea ; Lung Diseases ; NF-E2-Related Factor 2 ; Plasma ; Pulmonary Disease, Chronic Obstructive* ; Pulmonary Surfactant-Associated Protein D ; Respiratory Function Tests ; Vital Capacity

BACKGROUND: Mannose-binding lectin (MBL) deficiency leads to increased susceptibility to infection. We investigated whether serial changes in MBL levels are associated with the prognosis of patients diagnosed with septic shock, and correlated with cytokine levels. METHODS: We enrolled 131 patients with septic shock in the study. We analyzed the serum samples for MBL and cytokine levels at baseline and 7 days later. Samples on day 7 were available in 73 patients. RESULTS: We divided the patients with septic shock into four groups according to serum MBL levels ( < 1.3 µg/mL or ≥1.3 µg/mL) on days 1 and 7. Patients with low MBL levels on day 1 and high MBL levels on day 7 showed a favorable prognosis for 28-day survival (odds ratio, 1.96, 95% confidence interval, 1.10–2.87; p=0.087). The high MBL group on day 7 showed a significant decrease in monocyte chemoattractant protein 1, interleukin (IL)-1β, IL-6, IL-8, interferon-γ, and granulocyte macrophage colony-stimulating factor levels compared with the low MBL group on day 7. CONCLUSION: The increase in MBL levels of patients with septic shock may suggest a favorable prognosis and attenuate pro-inflammatory and anti-inflammatory responses.
Chemokine CCL2 ; Cytokines ; Granulocytes ; Humans ; Interleukin-6 ; Interleukin-8 ; Interleukins ; Macrophage Colony-Stimulating Factor ; Mannose-Binding Lectin* ; Prognosis ; Sepsis* ; Shock, Septic

The complement system is an innate immune defense machinery comprising components that deploy rapid immune responses and provide efficient protection against foreign invaders and unwanted host elements. The complement system is activated upon recognition of pathogenic microorganisms or altered self-cells by exclusive pattern recognition molecules (PRMs), such as collectins, ficolins and pentraxins. Recent accumulating evidence shows that the different classes of effector PRMs build up a co-operative network and exert synergistic effects on complement activation. In this review, we describe our updated view of the crosstalk between previously unlinked PRMs in complement activation and the potential pathogenic effects during infection and inflammation.
Collectins ; Complement Activation* ; Complement System Proteins* ; Inflammation

BACKGROUND: Human mannose-binding lectin (MBL) is a serum lectin taking part in the innate immunity by opsonizing various microorganisms for phagocytosis. The MBL serum concentration is affected by several single-nucleotide polymorphisms (SNPs) in the promoter region of the MBL2 gene. OBJECTIVE: The purpose of this study was to examine the relationship between MBL2 polymorphisms and atopic dermatitis (AD) susceptibility. METHODS: To examine whether the MBL2 SNPs are related to AD susceptibility, we examined 237 patients with AD and 94 controls by polymerase chain reaction (PCR)-restriction fragment length polymorphism and PCR-sequence specific primer analyses of four polymorphic loci: two (H/L and X/Y) within the promoter region and the other two (P/Q and A/B) within exon 1. MBL concentrations in the blood were estimated by ELISA. RESULTS: The prevalence of haplotype HYPB, leading to MBL deficiency, was significantly decreased in the AD patients compared to the controls (p=0.002), while the prevalence of haplotype HYPA was increased with a clear trend toward significance (p=0.056). The frequency of MBL2 LYPB/LXPA (odds ratio, 0.08; 95% confidence interval, 0.009~0.655; p=0.021) were significantly decreased in the AD patients. The blood log [total immunoglobulin E, IgE] levels of MBL2 HYPA/HYPA, HYPA/LYPA, HYPA/LYPB, HYPA/LYQA, and LYQA/LXPA haplotype pairs were significantly increased in the AD patients. CONCLUSION: The frequency of MBL2 HYPB haplotype was significantly decreased in the AD patients compared to the controls. The frequency of LYPB/LXPA had a possibly protective effect on AD. Moreover, the MBL2 HYPA haplotype pairs, which were related to higher blood total IgE levels, were possibly associated with extrinsic AD.
Dermatitis, Atopic* ; Enzyme-Linked Immunosorbent Assay ; Exons ; Haplotypes ; Humans ; Immunity, Innate ; Immunoglobulin E ; Immunoglobulins ; Mannose-Binding Lectin ; Phagocytosis ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Prevalence ; Promoter Regions, Genetic

Baker's asthma is the most prevalent occupational asthma, and IgE-mediated response is known as a major pathogenesis. However, recent studies have suggested the involvement of innate immune response because wheat flour contains bacterial endotoxins or lipopolysaccharides. To further understand a role of innate immune response in the development of work-related respiratory symptoms (WRS) in bakery workers, we investigated mannose-binding lectin (MBL), one of the initiating components of the complement cascade in a single cohort of bakery workers. A total of 373 bakery workers completed a questionnaire regarding WRS. The bakery workers were divided into 2 groups according to previous history of allergic rhinitis (AR)/bronchial asthma (BA): those with history of AR/BA (group I) and those without (group II). We measured serum MBL levels by using enzyme-linked immunosorbant assay and genotyped 4 single nucleotide polymorphisms of the MBL2 gene (226G>A in exon 1, -554G>C, -431A>C, and -225G>C in the promoter) by using TaqMan assays. Fifty-nine subjects (15.5%) were previously diagnosed with AR/BA, and 64 subjects (16.8%) complained of WRS. No significant differences were found in serum MBL levels between groups I and II. However, in group II subjects, but not in group I subjects, the serum MBL levels were significantly higher in bakery workers with WRS than in those without. In addition, the serum MBL levels were significantly different according to genetic polymorphisms of the MBL2 gene and its haplotypes. In conclusion, serum MBL, affected by genetic polymorphisms, may be associated with WRS in bakery workers with no previous history of AR/BA.
Asthma ; Asthma, Occupational ; Cohort Studies ; Complement System Proteins ; Endotoxins ; Exons ; Flour ; Haplotypes ; Immunity, Innate ; Lipopolysaccharides ; Mannose-Binding Lectin ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Rhinitis, Allergic ; Triticum

BACKGROUNDSurfactant protein-A (SP-A) contributes to the regulation of sepsis-induced acute kidney injury. In a previous study, we demonstrated that the expression of SP-A in the human renal tubular epithelial (HK-2) cells can be stimulated by lipopolysaccharide (LPS). The present study evaluated the possible signal-transducing mechanisms of LPS-induced SP-A biosynthesis in the HK-2 cells.

METHODSTetrazolium salt colorimetry (MTT) assay was used to detect cell viability of HK-2 cells after LPS stimulation on different time points. HK-2 cells were stimulated with 100 ng/ml of LPS for different durations to determine the effects of LPS on SP-A and toll-like receptor 4 (TLR4) messenger RNA (mRNA) expression, as well as phosphorylation of mitogen-activated/extracellular signal-regulated kinase (MEK) 1, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38MAPK), and nuclear factor-kappa B (NF-κB) inhibitor-alpha (IkB-α). Then, HK-2 cells were pretreated with CLI-095, a TLR4 inhibitor, to analyze mRNA and protein levels of SP-A and TLR4 and expression of NF-κB in the cytoplasm and nucleus of HK-2 before LPS exposure.

RESULTSHK-2 cells exposed to 100 ng/ml of LPS for 1, 6, and 24 h did not affect cell viability which showed no toxic effect of 100 ng/ml LPS on cells (P = 0.16); however, the biosynthesis of SP-A mRNA and protein in HK-2 cells was significantly increased (P = 0.02). As to the mechanism, LPS enhanced transmembrane receptor TLR4 protein expression. Sequentially, LPS time dependently augmented phosphorylation of MEK1, ERK1/2, and p38MAPK. In addition, levels of phosphorylated IκB-α and nuclear NF-κB were augmented with LPS exposure for 2 h. LPS-induced SP-A and TLR4 mRNA as well as NF-κB expression were significantly inhibited by pretreatment with CLI-095.

CONCLUSIONSThe present study exhibited that LPS can increase SP-A synthesis in human renal epithelial cells through sequentially activating the TLR4-related MEK1-ERK1/2-NF-κB-dependent pathway.

Cell Line ; Cell Survival ; drug effects ; physiology ; Colorimetry ; Humans ; Kidney ; cytology ; metabolism ; Lipopolysaccharides ; toxicity ; Mitogen-Activated Protein Kinase 1 ; metabolism ; Mitogen-Activated Protein Kinase 3 ; metabolism ; NF-kappa B ; metabolism ; Pulmonary Surfactant-Associated Protein A ; metabolism ; Sulfonamides ; pharmacology ; Tetrazolium Salts ; chemistry ; Toll-Like Receptor 4 ; antagonists & inhibitors ; metabolism

This study explored the relationship between the fractional exhaled nitric oxide (FeNO) level and the efficacy of inhaled corticosteroid (ICS) in asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) patients with different disease severity. A total of 127 ACOS patients with ACOS (case group) and 131 healthy people (control group) were enrolled in this study. Based on the severity of COPD, the ACOS patients were divided into: mild ACOS; moderate ACOS; severe ACOS; and extremely severe ACOS groups. We compared FeNO levels, pulmonary function parameters including percentage of forced expiratory volume in 1 second (FEV1) to predicted value (FEV1%pred), ratio of FEV1 to forced vital capacity (FEV1/FVC), inspiratory capacity to total lung capacity (IC/TLC) and residual volume to total lung capacity (RV/TLC), arterial blood gas parameters, including PH, arterial partial pressure of oxygen (PaO₂) and arterial partial pressure of carbon dioxide (PaCO₂), total serum immunoglobulin E (IgE), induced sputum eosinophil (EOS), plasma surfactant protein A (SP-A), plasma soluble receptor for advanced glycation end products (sRAGE), sputum myeloperoxidase (MPO), sputum neutrophil gelatinase-associated lipocalin (NGAL) and Asthma Control Test (ACT) scores, and COPD Assessment Test (CAT) scores. Compared with pre-treatment parameters, the FeNO levels, RV/TLC, PaCO₂, total serum IgE, induced sputum EOS, plasma SP-A, sputum MPO, sputum NGAL, and CAT scores were significantly decreased after 6 months of ICS treatment, while FEV1%pred, FEV1/FVC, IC/TLC, PH, PaO₂, plasma sRAGE, and ACT scores were significantly increased in ACOS patients with different disease severity after 6 months of ICS treatment. This finding suggests that the FeNO level may accurately predict the efficacy of ICS in the treatment of ACOS patients.
Animals ; Asthma ; Carbon Dioxide ; Cats ; Eosinophils ; Forced Expiratory Volume ; Glycosylation End Products, Advanced ; Humans ; Hydrogen-Ion Concentration ; Immunoglobulin E ; Immunoglobulins ; Inspiratory Capacity ; Lipocalins ; Lung Diseases, Obstructive ; Neutrophils ; Nitric Oxide* ; Oxygen ; Partial Pressure ; Peroxidase ; Plasma ; Pulmonary Disease, Chronic Obstructive ; Pulmonary Surfactant-Associated Protein A ; Residual Volume ; Sputum ; Total Lung Capacity ; Vital Capacity

OBJECTIVETo observe the levels of pulmonary surfactant proteins A and D (SP-A, SP-D) in bronchoalveolar lavage fluid (BALF) of children with pneumonia, and to explore their relationships with clinical characteristics.

METHODSThirty-five children with pneumonia were enrolled in this study. Differential cell counts were obtained by Countstar counting board. The levels of SP-A and SP-D in BALF were detected using ELISA.

RESULTSIn children with pneumonia, SP-D levels were significantly higher than SP-A levels (P<0.001). SP-D levels were negatively correlated with the neutrophil percentage in BALF (r(s)=-0.5255, P<0.01). SP-D levels in BALF in children with increased blood C-reactive protein levels (>8 mg/L) were significantly lower than in those with a normal level of C-reactive protein (P<0.05). Compared with those in children without wheezing, SP-D levels in children with wheezing were significantly lower (P<0.01). There was no correlation between SP-A levels and clinical characteristics.

CONCLUSIONSSP-D levels in BALF are significantly higher than SP-A levels, and have a certain correlation with clinical characteristics in children with pneumonia. As a protective factor, SP-D plays a more important role than SP-A in regulating the immune and inflammatory responses.

Bronchoalveolar Lavage Fluid ; chemistry ; C-Reactive Protein ; analysis ; Child ; Child, Preschool ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Infant ; Male ; Pneumonia ; metabolism ; Pulmonary Surfactant-Associated Protein A ; analysis ; Pulmonary Surfactant-Associated Protein D ; analysis

OBJECTIVETo investigate the correlation among serum levels of manning-binding lectin (MBL), MBL-associated serine proteases-2 (MASP-2), complement Cand high-sensitive C reactive protein (HsCRP) in patients with rheumatoid arthritis (RA).

METHODSFasting venous blood were collected from 50 RA patients (25 in active stage and 25 in remission) and 40 healthy subjects for detecting serum levels of MBL, MASP-2, complement Cand HsCRP using enzyme-linked immunosorbent assay (ELISA) and immune turbidity assay.

RESULTSThe serum levels of MBL and MASP-2 were significantly lower and HsCRP level was significantly higher in patients with RA (in both acute stage and remission) than in the healthy control group (P<0.05), but complement Clevel was similar between the RA patients and control group. Bivariate Pearson correlation analysis showed that in RA patients, MBL was positively correlated with MASP-2 level (r=0.550, P=0.001) and negatively with HsCRP (r=-0.323, P=0.022) but not correlated with C(r=-0.022, P=0.882); MASP-2 was negatively correlated with HsCRP (r=0.453, P=0.453) and was not correlated with C(r=0.049, P=0.738). ROC curve analysis revealed the largest area under curve (AUC) of HsCRP (0.844, P=0.001) and smaller AUCs of MBL (0.025, P=0.001) and MASP-2 (0.266, P=0.001). HsCRP had a much higher sensitivity (84%) than MBL (10%) and MASP-2 (40%) in the diagnosis of RA.

CONCLUSIONIn RA patients, MBL and MASP-2 are negatively correlated with HsCRP level. Serum MBL and MASP-2 levels decrease with the progression of joint injury in RA patients, suggesting their involvement in the pathological process of RA; but due to their low sensitivity, they are not appropriate indicators for evaluating the disease activity of RA.

Arthritis, Rheumatoid ; blood ; C-Reactive Protein ; analysis ; Case-Control Studies ; Complement C3 ; analysis ; Enzyme-Linked Immunosorbent Assay ; Humans ; Mannose-Binding Lectin ; blood ; Mannose-Binding Protein-Associated Serine Proteases ; analysis