Browsing by Subject "LUNG"

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  • Vaarno, Jenni; Myller, Jyri; Bachour, Adel; Koskinen, Heli; Bäck, Leif; Klockars, Tuomas; Koskinen, Anni (2020)
    Purpose We have previously demonstrated that dogs can be trained to distinguish the urine of patients with obstructive sleep apnea (OSA) from that of healthy controls based on olfaction. Encouraged by these promising results, we wanted to investigate if a detection dog could work as a screening tool for OSA. The objective of this study was to prospectively assess the dogs' ability to identify sleep apnea in patients with OSA suspicion. Methods Urine samples were collected from 50 patients suspected of having OSA. The urine sample was classified as positive for OSA when the patient had a respiratory event index of 5/h or more. The accuracy of two trained dogs in identifying OSA was tested in a prospective blinded setting. Results Both of the dogs correctly detected approximately half of the positive and negative samples. There were no statistically significant differences in the dogs' ability to recognize more severe cases of OSA, as compared to milder cases. Conclusion According to our study, dogs cannot be used to screen for OSA in clinical settings, most likely due to the heterogenic nature of OSA.
  • Kettunen, Eeva; Savukoski, Sauli; Salmenkivi, Kaisa; Böhling, Tom; Vanhala, Esa; Kuosma, Eeva; Anttila, Sisko; Wolff, Henrik (2019)
    BackgroundDeletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients' asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient's asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear.MethodsWe studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH.ResultsWe were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (>1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure ( 0.5 million f/g) (51.4% vs 16.7%; p=0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p=0.044, Fisher's Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen.ConclusionsWe found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count.
  • PRACTICAL Consortium; Bouras, Emmanouil; Karhunen, Ville; Gill, Dipender; Ahola-Olli, Ari; Mannikko, Minna; Auvinen, Juha; Herzig, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka; Lehtimäki, Terho; Salomaa, Veikko; Raitakari, Olli; Salmi, Marko; Jalkanen, Sirpa; Jarvelin, Marjo-Riitta; Tsilidis, Konstantinos K. (2022)
    Background Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.
  • Chen, Wen; Roslund, Kajsa; Fogarty, Christopher L.; Pussinen, Pirkko J.; Halonen, Lauri; Groop, Per-Henrik; Metsala, Markus; Lehto, Markku (2016)
    Hydrogen cyanide (HCN) has been recognized as a potential biomarker for non-invasive diagnosis of Pseudomonas aeruginosa infection in the lung. However, the oral cavity is a dominant production site for exhaled HCN and this contribution can mask the HCN generated in the lung. It is thus important to understand the sources of HCN production in the oral cavity. By screening of oral anaerobes for HCN production, we observed that the genus of Porphyromonas, Prevotella and Fusobacterium generated low levels of HCN in vitro. This is the first study to show that oral anaerobes are capable of producing HCN in vitro. Further investigations were conducted on the species of P. gingivalis and we successfully detected HCN production (0.9-10.9 ppb) in the headspace of three P. gingivalis reference strains (ATCC 33277, W50 and OMG 434) and one clinical isolate. From P. gingivalis ATCC 33277 and W50, a strong correlation between HCN and CO2 concentrations (r(s) = 0.89, p <0.001) was observed, indicating that the HCN production of P. gingivalis might be connected with the bacterial metabolic activity. These results indicate that our setup could be widely applied to the screening of in vitro HCN production by both aerobic and anaerobic bacteria.
  • Gruzieva, Olena; Merid, Simon Kebede; Chen, Su; Mukherjee, Nandini; Hedman, Anna M.; Almqvist, Catarina; Andolf, Ellika; Jiang, Yu; Kere, Juha; Scheynius, Annika; Soderhall, Cilia; Ullemar, Vilhelmina; Karmaus, Wilfried; Melen, Erik; Arshad, Syed Hasan; Pershagen, Goran (2019)
    There is emerging evidence on DNA methylation (DNAm) variability over time; however, little is known about dynamics of DNAm patterns during pregnancy. We performed an epigenome-wide longitudinal DNAm study of a well-characterized sample of young women from the Swedish Born into Life study, with repeated blood sampling before, during and after pregnancy (n = 21), using the Illumina Infinium MethylationEPIC array. We conducted a replication in the Isle of Wight third-generation birth cohort (n = 27), using the Infinium HumanMethylation450k BeadChip. We identified 196 CpG sites displaying intra-individual longitudinal change in DNAm with a false discovery rate (FDR) P <.05. Most of these (91%) showed a decrease in average methylation levels over the studied period. We observed several genes represented by > 3 differentially methylated CpGs: HOXB3, AVP, LOC100996291, and MicroRNA 10a. Of 36 CpGs available in the replication cohort, 17 were replicated, all but 2 with the same direction of association (replication P <.05). Biological pathway analysis demonstrated that FDR-significant CpGs belong to genes overrepresented in metabolism-related pathways, such as adipose tissue development, regulation of insulin receptor signaling, and mammary gland fat development. These results contribute to a better understanding of the biological mechanisms underlying important physiological alterations and adaptations for pregnancy and lactation.
  • Tuohinen, Suvi Sirkku; Skytta, Tanja; Huhtala, Heini; Virtanen, Vesa; Kellokumpu-Lehtinen, Pirkko-Liisa; Raatikainen, Pekka (2022)
    Background/Aim: Radiotherapy (RT) related myocardial changes were analyzed by deformation imaging echocardiography in this study. Patients and Methods: Ninety-nine breast cancer patients were studied at baseline, after chemotherapy, after RT, and three years after RT (3Y). Eighty patients received RT only, and twenty patients had right-sided breast cancer. Echocardiography included cyclic variation of the integrated backscatter in the septum (sCV) and posterior wall (pCV), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF). Results: In patients with left-sided breast cancer, sCV declined from 11.3??3.3 dB at baseline to 10.3??2.9 dB after RT (p=0.001). No changes were observed after chemotherapy (p=0.211) or in patients with right-sided breast cancer after RT (p=0.977). No other parameters declined after RT. The decline in sCV was independently associated with the left anterior descending coronary artery radiation dose (??=???0.290, p=0.020). Conclusion: In contrast to other parameters, sCV correlated with heart radiation dose.
  • Danielsen, Pernille Høgh; Knudsen, Kristina Bram; Štrancar, Janez; Umek, Polona; Koklič, Tilen; Garvas, Maja; Vanhala, Esa; Savukoski, Sauli; Ding, Yaobo; Madsen, Anne Mette; Jacobsen, Nicklas Raun; Weydahl, Ingrid Konow; Berthing, Trine; Poulsen, Sarah Søs; Schmid, Otmar; Wolff, Henrik; Vogel, Ulla (2020)
    Nanomaterial (NM) characteristics may affect the pulmonary toxicity and inflammatory response, including specific surface area, size, shape, crystal phase or other surface characteristics. Grouping of TiO2 in hazard assessment might be challenging because of variation in physicochemical properties. We exposed C57BL/6 J mice to a single dose of four anatase TiO2 NMs with various sizes and shapes by intratracheal instillation and assessed the pulmonary toxicity 1, 3, 28, 90 or 180 days post-exposure. The quartz DQ12 was included as benchmark particle. Pulmonary responses were evaluated by histopathology, electron microscopy, bronchoalveolar lavage (BAL) fluid cell composition and acute phase response. Genotoxicity was evaluated by DNA strand break levels in BAL cells, lung and liver in the comet assay. Multiple regression analyses were applied to identify specific TiO2 NMs properties important for the pulmonary inflammation and acute phase response. The TiO2 NMs induced similar inflammatory responses when surface area was used as dose metrics, although inflammatory and acute phase response was greatest and more persistent for the TiO2 tube. Similar histopathological changes were observed for the TiO2 tube and DQ12 including pulmonary alveolar proteinosis indicating profound effects related to the tube shape. Comparison with previously published data on rutile TiO2 NMs indicated that rutile TiO2 NMs were more inflammogenic in terms of neutrophil influx than anatase TiO2 NMs when normalized to total deposited surface area. Overall, the results suggest that specific surface area, crystal phase and shape of TiO2 NMs are important predictors for the observed pulmonary effects of TiO2 NMs.
  • Gupta, Richa; van Dongen, Jenny; Fu, Yu; Abdellaoui, Abdel; Tyndale, Rachel F.; Velagapudi, Vidya; Boomsma, Dorret I.; Korhonen, Tellervo; Kaprio, Jaakko; Loukola, Anu; Ollikainen, Miina (2019)
    BackgroundDNA methylation alteration extensively associates with smoking and is a plausible link between smoking and adverse health. We examined the association between epigenome-wide DNA methylation and serum cotinine levels as a proxy of nicotine exposure and smoking quantity, assessed the role of SNPs in these associations, and evaluated molecular mediation by methylation in a sample of biochemically verified current smokers (N=310).ResultsDNA methylation at 50 CpG sites was associated (FDR
  • Kilpeläinen, Tuomas; Pogodin-Hannolainen, Dimitri; Kemppainen, Kimmo; Talala, Kirsi; Raitanen, Jani; Taari, Kimmo; Kujala, Paula; Tammela, Teuvo L. J.; Auvinen, Anssi (2017)
    Purpose: Screening for prostate cancer remains controversial, although ERSPC (European Randomized Study of Screening for Prostate Cancer) showed a 21% relative reduction in prostate cancer mortality. The Finnish Randomized Study of Screening for Prostate Cancer, which is the largest component of ERSPC, demonstrated a statistically nonsignificant 16% mortality benefit in a separate analysis. The purpose of this study was to estimate the degree of contamination in the control arm of the Finnish trial. Materials and Methods: Altogether 48,295 and 31,872 men were randomized to the control and screening arms, respectively. The screening period was 1996 to 2007. The extent of prostate specific antigen testing was analyzed retrospectively using laboratory databases. The incidence of T1c prostate cancer (impalpable prostate cancer detected by elevated prostate specific antigen) was determined from the national Finnish Cancer Registry. Results: Approximately 1.4% of men had undergone prostate specific antigen testing 1 to 3 years before randomization. By the first 4, 8 and 12 years of follow-up 18.1%, 47.7% and 62.7% of men in the control arm had undergone prostate specific antigen testing at least once and in the screening arm the proportions were 69.8%, 81.1% and 85.2%, respectively. The cumulative incidence of T1c prostate cancer was 6.1% in the screening arm and 4.5% in the control arm (RR 1.21, 95% CI 1.13-1.30). Conclusions: A large proportion of men in the control arm had undergone a prostate specific antigen test during the 15-year followup. Contamination is likely to dilute differences in prostate cancer mortality between the arms in the Finnish screening trial.
  • Vuori-Holopainen, Elina; Salo, Eeva; Saxen, Harri; Hedman, Klaus; Hyypiä, Timo; Lahdenperä, Raija; Leinonen, Maija; Tarkka, Eveliina; Vaara, Martti; Peltola, Heikki (2002)
    Childhood pneumonia is usually treated without determining its etiology. The causative organism can be isolated from specimens of blood, empyema fluid, or lung aspirate, but this is rarely done. The potential of transthoracic needle aspiration for identification of causative agents was tested with use of modern microbiological methods. Aspiration was performed for 34 children who had radiological signs compatible with community-acquired pneumonia and had alveolar consolidation. In addition to bacterial and viral cultures and viral antigen detection, nucleic acid detection for common respiratory pathogens was performed on aspirate specimens. Aspiration disclosed the etiology in 20 (59%) of 34 cases overall and in 18 (69%) of 26 patients from whom a representative specimen was obtained. Aspiration's advantages are high microbiological yield and a relatively low risk of a clinically significant adverse event. Aspiration should be used if identification of the causative agent outweighs the modest risk of the procedure.
  • Ramasamy, Adaikalavan; Kuokkanen, Mikko; Vedantam, Sailaja; Gajdos, Zofia K.; Alves, Alexessander Couto; Lyon, Helen N.; Ferreira, Manuel A. R.; Strachan, David P.; Zhao, Jing Hua; Abramson, Michael J.; Brown, Matthew A.; Coin, Lachlan; Dharmage, Shyamali C.; Duffy, David L.; Haahtela, Tari; Heath, Andrew C.; Janson, Christer; Kahonen, Mika; Khaw, Kay-Tee; Laitinen, Jaana; Le Souef, Peter; Lehtimaki, Terho; Madden, Pamela A. F.; Marks, Guy B.; Martin, Nicholas G.; Matheson, Melanie C.; Palmer, Cameron D.; Palotie, Aarno; Pouta, Anneli; Robertson, Colin F.; Viikari, Jorma; Widen, Elisabeth; Wjst, Matthias; Jarvis, Deborah L.; Montgomery, Grant W.; Thompson, Philip J.; Wareham, Nick; Eriksson, Johan; Jousilahti, Pekka; Laitinen, Tarja; Pekkanen, Juha; Raitakari, Olli T.; O'Connor, George T.; Salomaa, Veikko; Jarvelin, Marjo-Riitta; Hirschhorn, Joel N.; Australian Asthma Genetics (2012)
  • Laulajainen-Hongisto, Anu; Lyly, Annina; Hanif, Tanzeela; Dhaygude, Kishor; Kankainen, Matti; Renkonen, Risto; Donner, Kati; Mattila, Pirkko; Jartti, Tuomas; Bousquet, Jean; Kauppi, Paula; Toppila-Salmi, Sanna (2020)
    Genome wide association studies (GWASs) have revealed several airway disease-associated risk loci. Their role in the onset of asthma, allergic rhinitis (AR) or chronic rhinosinusitis (CRS), however, is not yet fully understood. The aim of this review is to evaluate the airway relevance of loci and genes identified in GWAS studies. GWASs were searched from databases, and a list of loci associating significantly (p <10(-8)) with asthma, AR and CRS was created. This yielded a total of 267 significantly asthma/AR-associated loci from 31 GWASs. No significant CRS -associated loci were found in this search. A total of 170 protein coding genes were connected to these loci. Of these, 76/170 (44%) showed bronchial epithelial protein expression in stained microscopic figures of Human Protein Atlas (HPA), and 61/170 (36%) had a literature report of having airway epithelial function. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation analyses were performed, and 19 functional protein categories were found as significantly (p <0.05) enriched among these genes. These were related to cytokine production, cell activation and adaptive immune response, and all were strongly connected in network analysis. We also identified 15 protein pathways that were significantly (p <0.05) enriched in these genes, related to T-helper cell differentiation, virus infection, JAK-STAT signaling pathway, and asthma. A third of GWAS-level risk loci genes of asthma or AR seemed to have airway epithelial functions according to our database and literature searches. In addition, many of the risk loci genes were immunity related. Some risk loci genes also related to metabolism, neuro-musculoskeletal or other functions. Functions overlapped and formed a strong network in our pathway analyses and are worth future studies of biomarker and therapeutics.
  • Nissinen, R.; Leirisalo-Repo, M; Nieminen, A. M.; Halme, L.; Färkkilä, M.; Palosuo, T.; Vaarala, O. (2004)
    Objectives: To determine whether inflammation in the gut associated immune system is activated in rheumatoid arthritis ( RA). The expression of chemokine receptor- (CCR4, CCR5) and cytokine- ( interleukin (IL) 2, IL10, interferon gamma (IFNgamma), tumour necrosis factor alpha (TNFalpha), and transforming growth factor beta (TGFbeta)) specific mRNA in intestinal biopsy samples from patients with RA was examined. Methods: Duodenal biopsy samples from 13 patients with RA and 15 control subjects were studied. The mRNA expression of CCR4, CCR5, IL2, IL10, IFNgamma, TNFalpha, and TGFb in intestinal biopsy samples was demonstrated by real time quantitative reverse transcriptase-polymerase chain reaction. Results: The mRNA expression of CCR4, CCR5, and IL10 in intestinal biopsy samples was increased in patients with RA in comparison with control subjects ( p = 0.001, p = 0.046, p = 0.019). No difference in the expression levels of IL2, IFNgamma, TNFalpha, or TGFbeta was seen between patients with RA and controls. Conclusions: The increased intestinal mRNA expression of IL10, CCR5, and CCR4 suggests that gut associated immune cells are activated in patients with RA.
  • Rydman, Elina M.; Ilves, Marit; Koivisto, Antti J.; Kinaret, Pia A. S.; Fortino, Vittorio; Savinko, Terhi S.; Lehto, Maili T.; Pulkkinen, Ville; Vippola, Minnamari; Hämeri, Kaarle J.; Matikainen, Sampsa; Wolff, Henrik; Savolainen, Kai M.; Greco, Dario; Alenius, Harri (2014)
  • Reichhardt, Martin Parnov; Messing, Marcel; Andersson, Sture; Kolho, Kaija-Leena; Meri, Seppo (2021)
    The first months of life represent a crucial time period for an infant. Alongside establishing the early microbiome, the mucosal immunological homeostasis is being developed. Both processes may be perturbed in prematurely born infants. The glycoprotein SALSA plays a role in mucosal inflammation and microbial clearance. It is one of the most abundant molecules on the intestinal mucosal surfaces in early life. SALSA binds to many types of microbes and host defence molecules like IgA, C1q and collectin molecules. We here describe the development in faecal SALSA levels during the first three months of life. During these 90 days, the median SALSA level in full-term babies decreased from 1100 mu g/mL (range 49-17 000 mu g/mL) to 450 mu g/mL (range 33-1000 mu g/mL). Lower levels of SALSA were observed in prematurely born infants in the same time period. Our novel observation thus indicates an impact of prematurity on an important component of the infant intestinal immune system. Changes in SALSA in early life may have an effect on the early establishment of the human microbiome.
  • Tomasovic, Ana; Kurrle, Nina; Wempe, Frank; De-Zolt, Siike; Scheibe, Susan; Koli, Katri; Serchinger, Martin; Schnuetgen, Frank; Sueruen, Duran; Sterner-Kock, Anja; Weissmann, Norbert; von Meichner, Harald (2017)
    Latent transforming growth factor beta binding protein 4 (LTBP4) belongs to the fibrillin/LTBP family of proteins and plays an important role as a structural component of extracellular matrix (ECM) and local regulator of TGF beta signaling. We have previously reported that Ltbp4S knock out mice (Ltbp4S-/-) develop centrilobular emphysema reminiscent of late stage COPD, which could be partially rescued by inactivating the antioxidant protein Sestrin 2 (Sesn2). More recent studies showed that Sesn2 knock out mice upregulate Pdgfr beta-controlled alveolar maintenance programs that protect against cigarette smoke induced pulmonary emphysema. Based on this, we hypothesized that the emphysema of Ltbp4S-/- mice is primarily caused by defective Pdgfr beta signaling. Here we show that LTBP4 induces Pdgfr beta signaling by inhibiting the antioxidant Nr12/Keap1 pathway in a TGF beta-dependent manner. Overall, our data identified Ltbp4 as a major player in lung remodeling and injury repair. (C) 2016 The Authors. Published by Elsevier B.V.
  • Koljonen, Virve; Sahi, Helka; Bohling, Tom; Mäkisalo, Heikki (2016)
    Malignant tumours are the foremost complications of immunosuppressive treatment. They are a major challenge for organ transplant recipients and their treating physicians. This paper reviews the aetiology and current treatment of an unusual neuroendocrine skin cancer, Merkel cell carcinoma (MCC), caused by a Merkel cell polyomavirus infection. MCC occurs more frequently than expected in immunosuppressed subjects, especially in organ transplant recipients. The current literature comprises reports of 79 organ transplant recipients with MCC. The risk of MCC in organ transplant recipients is increased up to 66-182-fold compared with the general population. In addition to the increased risk of developing MCC, immunosuppressed individuals have poorer MCC-specific survival. The aim of this review article is to familiarize organ transplant doctors with this unique and clinically challenging skin cancer, and to provide recent data on the diagnosis and current treatment recommendations for an immunosuppressed population.
  • Hadrup, Niels; Knudsen, Kristina Bram; Berthing, Trine; Wolff, Henrik; Bengtson, Stefan; Kofoed, Christian; Espersen, Roall; Hojgaard, Casper; Winther, Jakob Rahr; Willemoes, Martin; Wedin, Irene; Nuopponen, Markus; Alenius, Harri; Norppa, Hannu; Wallin, Hakan; Vogel, Ulla (2019)
    We studied if the pulmonary and systemic toxicity of nanofibrillated celluloses can be reduced by carboxylation. Nanofibrillated celluloses administered at 6 or 18 mu g to mice by intratracheal instillation were: 1) FINE NFC, 2-20 mu m in length, 2-15 nm in width, 2) AS (-COOH), carboxylated, 0.5-10 mu m in length, 4-10 nm in width, containing the biocide BIM MC4901 and 3) BIOCID FINE NFC: as (1) but containing BIM MC4901. FINE NFC administration increased neutrophil influx in BAL and induced SAA3 in plasma. AS (-COOH) produced lower neutrophil influx and systemic SAA3 levels than FINE NFC. Results obtained with BIOCID FINE NFC suggested that BIM MC4901 biocide did not explain the lowered response. Increased DNA damage levels were observed across materials, doses and time points. In conclusion, carboxylation of nanofibrillated cellulose was associated with reduced pulmonary and systemic toxicity, suggesting involvement of OH groups in the inflammatory and acute phase responses.
  • Liekkinen, Juho; Enkavi, Giray; Javanainen, Matti; Olmeda, Barbara; Pérez-Gil, Jesús; Vattulainen, Ilpo (2020)
    Surfactant protein B (SP-B) is essential in transferring surface-active phospholipids from membrane-based surfactant complexes into the alveolar air-liquid interface. This allows maintaining the mechanical stability of the surfactant film under high pressure at the end of expiration; therefore, SP-B is crucial in lung function. Despite its necessity, the structure and the mechanism of lipid transfer by SP-B have remained poorly characterized. Earlier, we proposed higher-order oligomerization of SP-B into ring-like supramolecular assemblies. In the present work, we used coarse-grained molecular dynamics simulations to elucidate how the ring-like oligomeric structure of SP-B determines its membrane binding and lipid transfer. In particular, we explored how SP-B interacts with specific surfactant lipids, and how consequently SP-B reorganizes its lipid environment to modulate the pulmonary surfactant structure and function. Based on these studies, there are specific lipid-protein interactions leading to perturbation and reorganization of pulmonary surfactant layers. Especially, we found compelling evidence that anionic phospholipids and cholesterol are needed or even crucial in the membrane binding and lipid transfer function of SP-B. Also, on the basis of the simulations, larger oligomers of SP-B catalyze lipid transfer between adjacent surfactant layers. Better understanding of the molecular mechanism of SP-B will help in the design of therapeutic SP-B-based preparations and novel treatments for fatal respiratory complications, such as the acute respiratory distress syndrome. (C) 2020 The Author(s). Published by Elsevier Ltd.
  • Koivisto, Antti J.; Palomaki, Jaana E.; Viitanen, Anna-Kaisa; Siivola, Kirsi M.; Koponen, Ismo K.; Yu, Mingzhou; Kanerva, Tomi S.; Norppa, Hannu; Alenius, Harri T.; Hussein, Tareq; Savolainen, Kai M.; Hameri, Kaarle J. (2014)