The status of IPF in the Japanese population was clarified for the first time through our study. Our results showed that in men, the incidence of death caused by acute exacerbation was higher and that caused by cardiovascular disease was lower in Japan than in Western countries. These results may suggest ethnic differences in IPF.

Surfactant proteins A (SP-APulmonary surfactant is a complex mixture of lipids and proteins that functions to keep alveoli from collapsing at the end of expiration (1). Surfactant proteins A (SP-A) 1 and D (SP-D) are glycoprotein constituents of lung surfactant (2). SP-A and SP-D belong to the collectin subgroup of the C-type lectin superfamily along with mannose-binding proteins A and C, conglutinin, and CL43 (3). These proteins possess similar characteristic structures consisting of a short intersubunit disulfide forming the NH 2 terminus region, a collagen-like domain, a coiled-coil motif neck domain, and a carbohydrate recognition domain (CRD) (2). The CRD region of SP-A is essential for dipalmitoylphosphatidylcholine and galactosylceramide binding, liposome aggregation, the inhibitory effect on lipid secretion, and the augmentation of lipid uptake by alveolar type II cells (4 -11). Likewise, the CRD region of SP-D functions in the recognition of the ligands phosphatidylinositol and glucosylceramide (12,13). In addition to their interaction with lipids and alveolar type II cells, lung collectins interact with macrophages (14 -16) and enhance phagocytosis of a wide spectrum of microorganism (17-25). Lung collectins are now thought to be important components of the innate immune system of the lung (26 -28).Studies with transgenic mice provide strong support for a role of pulmonary collectins in host defense properties. Mice homozygous for null alleles of SP-A exhibit increased susceptibility to group B streptococcal and Pseudomonas aeruginosa infections (29 -31). These mice clear the bacteria from the lungs at a slower rate than wild-type mice. Phagocytosis of P. aeruginosa by alveolar macrophages in SP-A Ϫ/Ϫ mice is also significantly decreased (30). Coadministration of SP-A with bacteria into the airway of SP-A Ϫ/Ϫ mice enhance phagocytosis of the bacteria by alveolar macrophages. Secretion of proinflammatory cytokines into the alveolar space is significantly elevated in SP-A Ϫ/Ϫ mice compared with SP-A ϩ/ϩ mice after intratracheal challenge with P. aeruginosa. These studies suggest that SP-A modulates innate immune responses by several different mechanisms. Although these in vivo studies explicitly indicate that SP-A plays a crucial role in host defense of the lung, the molecular basis of SP-A-mediated modification of inflammatory responses remains to be elucidated.Lipopolysaccharide (LPS), derived from Gram-negative bacteria, is a potent stimulator of inflammation (32). Smooth LPS is composed of O-antigen, core oligosaccharides, and lipid A, while rough LPS lacks O-antigen and a part of the core oligosaccharides (33). The cellular responses to physiological amounts of LPS depend on membrane CD14 that is phosphatidylinositol-anchored to the plasma membrane of myeloid cells (34). A soluble form of CD14 which exists in serum also facilitates the responsiveness of the cells to LPS (35,36). The principal role of CD14 is to bind LPS, but how CD14 acts in transmitting LPS signal remains to be resolved. Recently, ...

Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis.

To find a less-invasive and lung-specific clinical biomarker, we measured serum levels of surfactant proteins A and D (SP-A and SP-D) by sandwich enzyme-linked immunosorbent assays in 42 patients with progressive systemic sclerosis (PSS) to evaluate their significance in relation to the presence of interstitial lung disease (ILD) and to assess their diagnostic merits. The patients were divided into two groups based on findings by chest computed tomography (CT): 30 patients with ILD (CT-positive ILD group), and 12 patients without any lung abnormalities (CT-negative ILD group). The CT-positive ILD group was further divided into two groups: 24 patients with ILD detectable by chest plain radiography (X-ray-positive ILD group) and six patients with ILD showing no abnormality (X-ray-negative ILD group). The levels of SP-A and SP-D in sera were significantly higher in the CT-positive ILD group than in the CT-negative ILD group. They were also significantly higher in the X-ray-positive ILD group than in the CT-negative ILD group. In the X-ray-negative ILD group, their levels were higher than those of the CT-negative ILD group. We next estimated sensitivity and specificity of SP-A, SP-D, and X-ray for detecting ILD on CT. Sensitivity of SP-D was high (77%) as well as that of X-ray (80%), whereas SP-A showed a low sensitivity (33%). Remarkably, five of six patients in the X-ray-negative ILD group showed SP-D concentrations over its cut-off level, thereby demonstrating that an SP-D assay contributes to the detection of ILD overlooked by X-ray. Moreover, a combination of X-ray and SP-D dramatically increases sensitivity to 97%. Specificity of SP-A, SP-D, and X-ray to the CT-negative ILD group was 100%, 83%, and 100%, respectively. In conclusion, this study indicates that elevated levels of serum SP-A and SP-D reflect well the presence of ILD and that the combination of SP-D and X-ray contributes to reduce the risk of clinicians overlooking ILD complicated by PSS, although a repetition in another set of subjects is needed to confirm these indications.

The abundant and restricted expression of surfactant proteins SP-A and SP-D within the lung makes these collectins specific markers for lung diseases. The measurement of SP-A and SP-D in amniotic fluids and tracheal aspirates reflects lung maturity and the production level of the lung surfactant in infants with respiratory distress syndrome (RDS). The SP-A concentrations in bronchoalveolar lavage (BAL) fluids are significantly decreased in patients with acute respiratory distress syndrome (ARDS) and also in patients at risk to develop ARDS. The prominent increase of these proteins in BAL fluids and sputum is diagnostic for pulmonary alveolar proteinosis (PAP). The concentrations of SP-A and SP-D in BAL fluids from patients with idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with collagen vascular diseases (IPCD) are rather lower than those in healthy controls and the SP-A/phospholipid ratio may be a useful marker of survival prediction. SP-A and SP-D appear in the circulation in specific lung diseases. Their serum concentrations significantly increase in patients with PAP, IPF and IPCD. The successive monitoring of serum levels of SP-A and SP-D may predict the disease activity. The serum SP-A levels increase in patients with ARDS. SP-A is also a marker for lung adenocarcinomas and can be used to differentiate lung adenocarcinomas from other types and metastatic cancers from other origins, and to detect metastasis of lung adenocarcinomas.

Gangliosides are glycosphingolipids found on the cell surface. They act as recognition molecules or signal modulators and regulate cell proliferation and differentiation. N-glycolylneuraminic acid (NeuGc)-containing gangliosides have been detected in some neoplasms in humans, although they are usually absent in normal human tissues. Our aim was to evaluate the presence of NeuGc-containing gangliosides including GM3 (NeuGc) and assess their relationship with the prognosis of non-small-cell lung cancer (NSCLC). NeuGc-containing ganglioside expression in NSCLC tissues was analyzed immunohistochemically using the mouse monoclonal antibody GMR8, which is specific for gangliosides with NeuGc alpha 2,3Gal-terminal structures. On the basis of NeuGc-containing ganglioside expression, we performed survival analysis. We also investigated the differences in the effects of GM3 (N-acetylneuraminic acid [NeuAc]) and GM3 (NeuGc) on inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase in A431 cells. As a result, the presence of NeuGc-containing gan-gliosides was evident in 86 of 93 (93.5%) NSCLC samples. The NSCLC patients with high NeuGc-containing ganglioside expression had a low overall survival rate and a significantly low progression free survival rate. In the in vitro study, the inhibitory effect of GM3 on EGFR tyrosine kinase in A431 cells after exposure to GM3 (NeuGc) was lower than that after exposure to GM3 (NeuAc). In conclusion, NeuGc-containing gangliosides including GM3 (NeuGc) are widely expressed in NSCLC, and NeuGc-containing ganglioside expression is associated with patient survival. The difference in the effects of GM3 (NeuGc) and GM3 (NeuAc) on the inhibition of EGFR tyrosine kinase might contribute to improvement in the prognosis of NSCLC patients. (Cancer Sci 2013; 104: 43-47) L ung cancer is the most frequently diagnosed major cancer worldwide. (1) The World Health Organization classification of lung cancer identifies squamous cell carcinoma, adenocarci-noma, large cell carcinoma and small cell carcinoma as its four major types. These tumors are commonly divided into small-cell lung cancer and non-small-cell lung cancer (NSCLC) depending on differences in their biology and treatment. The low rate of cure for NSCLC can be attributed to the high metastasis rate at diagnosis and the lack of effective treatments to cure such a metastatic disease. Gangliosides are ubiquitous membrane-associated glycos-phingolipids containing at least one sialic acid residue. They act as recognition molecules or signal modulators and regulate cell proliferation and differentiation. (2,3) Delay in cell growth of the human epidermoid carcinoma cell line A431 is caused by GM3 (N-acetylneuraminic acid [NeuAc])-mediated inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase. (4) GM3 is a ganglioside that binds to the extracellular domain of EGFR and inhibits its dimerization without inhibiting ligand binding. (5) Kawashima et al. described the significance of carbohydrate-carbohydrate interactions betw...

Surfactant Protein A (SP-APulmonary surfactant protein A (SP-A) 1 is a prominent member of the collectin subgroup of the C-type lectin superfamily that also includes the closely related collectins surfactant protein D (SP-D), serum mannose-binding protein, bovine serum conglutinin, and CL-43 (1). SP-A is an abundant component of pulmonary surfactant, a complex mixture of lipids and proteins that reduces surface tension in the alveoli during expiration (2). A growing body of evidence demonstrates that SP-A plays an important role regulating the innate host defense system within the lung (3). Functional deletion of the SP-A gene from the mouse genome provides important evidence establishing the regulatory role of the protein in innate immunity in vivo (4 -6). The interaction of SP-A with immune cells can occur through ligation of a number of cell surface receptors that include the lipopolysaccharide-binding protein, CD14 (7), a 210-kDa protein, SPR 210 (7), a complement binding protein, C1qR (8), CD91/calreticulin (9), and SIRP␣ (10). In addition to recognition of immune cells, the protein can bind a variety of pulmonary pathogens, including Pseudomonas, Escherichia, Mycobacterium, Mycoplasma, Candida, Aspergillus, Histoplasma, and Influenza species (summarized in Ref. 3). For some organisms, SP-A functions as an opsonin and enhances phagocytosis (11,12). The interactions of SP-A with microorganisms and host cells are complex and incompletely understood. In some cases the ligation of microbes (or derived ligands) and immune effector cells leads to amplification of inflammatory responses (13, 14), whereas in others the inflammatory responses are markedly attenuated (7,15,16). The emerging picture is consistent with the nature of the foreign ligand and the predisposed state of the responding immune cell, both playing important roles in dictating the final inflammatory response of the host. In addition to modulating the actions of inflammatory cells SP-A and SP-D can also exert a direct antimicrobial effect upon several Gram-negative bacteria (17, 18) and Histoplasma capsulatum (18) by increasing membrane permeability. The effects upon Gram-negative cells appear to be mediated via surface lipopolysaccharide binding. The surface-binding molecule for Histoplasma is not known but could be a glycoconjugate.In this report we have focused on the interactions of SP-A with Mycoplasma pneumoniae. Unlike Gram-negative bacteria mycoplasma lack lipopolysaccharides and are likely to have novel ligands for SP-A. M. pneumoniae is an important human pathogen that causes primary atypical pneumonia and other airway diseases, including tracheobronchitis and pharyngitis. Infection by the organism can also seriously exacerbate asthma (19,20). Recent evidence also demonstrates the presence of the organism in a subset of chronic asthmatics suggesting that it may have a contributing role in the etiology of the disease (21). Several studies have previously implicated SP-A as a modulator of macrophage-dependent killing of the mouse pathogen...

Pulmonary surfactant, a complex of lipids and proteins, functions to keep alveoli from collapsing at expiration. Surfactant proteins A (SP-A) and D (SP-D) belong to the collectin family and play pivotal roles in the innate immunity of the lung. Pulmonary collectins directly bind with broad specificities to a variety of microorganism and possess anti-microbial effects. These proteins also exhibit both inflammatory and anti-inflammatory functions, which occur through interactions with pattern recognition receptors including Toll-like receptor and CD14, signal inhibitory regulatory protein alpha and a receptor complex of calreticulin and CD91. The collectins enhance phagocytosis of microbes by macrophages through opsonic and/or non-opsonic activities. The proteins stimulate cell surface expression of phagocytic receptors including scavenger receptor A and mannose receptor. Since the expression of SP-A and SP-D is abundant and restricted within the lung, the proteins are now clinically used as biomarkers for lung diseases. The levels of SP-A and SP-D in bronchoalveolar lavage fluids, amniotic fluids, tracheal aspirates and pleural effusions reflect alterations in alveolar compartments and epithelium, and lung maturity. The determination of SP-A and SP-D in sera is a non-invasive and useful tool for understanding some pathological changes of the lung in the diseases, including pulmonary fibrosis, collagen vascular diseases complicated with interstitial lung disease, pulmonary alveolar proteinosis, acute respiratory distress syndrome and radiation pneumonitis.