A review of big data technology and its application in cancer care.

The development of modern medical devices and information technology has led to a rapid growth in the amount of data available for health protection information, with the concept of medical big data emerging globally, along with significant advances in cancer care relying on data-driven approaches. However, outstanding issues such as fragmented data governance, low-quality data specification, and data lock-in still make sharing challenging. Big data technology provides solutions for managing massive heterogeneous data while combining artificial intelligence (AI) techniques such as machine learning (ML) and deep learning (DL) to better mine the intrinsic connections between data. This paper surveys and organizes recent articles on big data technology and its applications in cancer, dividing them into three different types to outline their primary content and summarize their critical role in assisting cancer care. It then examines the latest research directions in big data technology in cancer and evaluates the current state of development of each type of application. Finally, current challenges and opportunities are discussed, and recommendations are made for the further integration of big data technology into the medical industry in the future.

CCR5 drives NK cell-associated airway damage in pulmonary ischemia-reperfusion injury.

Primary graft dysfunction (PGD) limits clinical benefit after lung transplantation, a life-prolonging therapy for patients with end-stage disease. PGD is the clinical syndrome resulting from pulmonary ischemia-reperfusion injury (IRI), driven by innate immune inflammation. We recently demonstrated a key role for NK cells in the airways of mouse models and human tissue samples of IRI. Here, we used 2 mouse models paired with human lung transplant samples to investigate the mechanisms whereby NK cells migrate to the airways to mediate lung injury. We demonstrate that chemokine receptor ligand transcripts and proteins are increased in mouse and human disease. CCR5 ligand transcripts were correlated with NK cell gene signatures independently of NK cell CCR5 ligand secretion. NK cells expressing CCR5 were increased in the lung and airways during IRI and had increased markers of tissue residency and maturation. Allosteric CCR5 drug blockade reduced the migration of NK cells to the site of injury. CCR5 blockade also blunted quantitative measures of experimental IRI. Additionally, in human lung transplant bronchoalveolar lavage samples, we found that CCR5 ligand was associated with increased patient morbidity and that the CCR5 receptor was increased in expression on human NK cells following PGD. These data support a potential mechanism for NK cell migration during lung injury and identify a plausible preventative treatment for PGD.

Highly efficient solar-absorber composite material based on tetrapyridylporphyrin for water evaporation and thermoelectric power generation.

Photothermal materials based on organic small molecules have the characteristics of structural diversity and easy modification for solar-driven water evaporation and power generation technology. However, there still exist limitations, such as the utilization of solar energy and photostability. Therefore, it is the focus of current research to design organic photothermal materials with excellent photothermal stability, strong solar absorption capacity, and high photothermal conversion efficiency. Herein, photothermal conversion materials based on tetrapyridylporphyrin (TPyP) is studied, which possesses polypyrrole macrocyclic framework (18π electrons), which makes it exhibit strong absorption in the 300-800 nm region with high photothermal conversion. The interfacial-heating evaporation system based on polyurethane (PU) foam loaded with TPyP was prepared, whose solar-to-vapor conversion efficiency and vapor evaporation rate of PU + TPyP foam solar energy reached 56% and 0.81 kg m-2 h-1, respectively. In addition, TPyP-loaded solar evaporator equipped with abundant microchannels for water flow are integrated with thermoelectric devices, thus achieving an evaporation rate and voltage as high as 0.69 kg m-2 h-1 and 60 mV under 1 kW m-2 solar irradiation, respectively. The successful application of TPyP in water evaporation and power generation effectively addresses the difficulties faced in the process of using organic small molecule photothermal materials to solve the energy crisis.

IL-37 alleviates liver granuloma caused by Schistosoma japonicum infection by inducing alternative macrophage activation.

BACKGROUND: Hepatic macrophages regulate liver granuloma formation and fibrosis caused by infection with Schistosoma japonicum, with the manner of regulation dependent on macrophage activation state. Interleukin (IL)-37 may have immunomodulatory effects on macrophages. However, whether IL-37 can affect liver granuloma formation and fibrosis by affecting the polarization of macrophages in S. japonicum infection remains unclear. The aim of this study was to investigate IL-37-affected macrophage polarization in liver granuloma formation and fibrosis in S. japonicum infection. METHODS: An enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of IL-37 in the serum of patients with acute S. japonicum infection and in the serum of healthy people. Recombinant IL-37 (rIL-37), CPP-IgG2Fc-IL-37 and no CPP-IgG2Fc-IL-37 proteins were injected into S. japonicum-infected mice every 3 days for a total of 6 times from day 24 post infection onwards. Subsequently, ELISA, quantitative reverse transcription-PCR, fluorescence-activated cell sorting and western blot were used to analyze whether IL-37 inhibits the formation of liver granulomas and the development of liver fibrosis by regulating the phenotypic transition of macrophages. Finally, the three IL-37 proteins and SIS3, a Smad3 inhibitor, were co-cultured in mouse peritoneal macrophages to explore the mechanism underlying the promotion of the polarization of M0 macrophages to the M2 phenotype by IL-37. RESULTS: Serum IL-37 levels were upregulated in schistosomiasis patients, and this increased level of IL-37 protein apparently alleviated the liver granuloma of mice in infection models. It also could induce liver and peritoneal macrophages to polarize to the M2 phenotype in S. japonicum-infected mice. The S. japonicum-infected mice injected with CPP-IgG2Fc-IL-37 group exhibited the most obvious improvement in inflammatory reaction against the liver granuloma. The number and ratio of M2 macrophages in the liver and peritoneal cavity were significantly higher in the three IL-37 protein groups, especially in the CPP-IgG2Fc-IL-37 group, compared to the controls. Similar results were also found regarding liver function damage. IL-37 induced macrophage M2 polarization by promoting AMP-activated protein kinase (AMPK) phosphorylation in vitro. Among all groups, the activation of AMPK was most significant in the CPP-IgG2Fc-IL-37 group, and it was found that SMAD3 could enhance the anti-inflammatory function of IL-37. CONCLUSIONS: The results show that IL-37 was able to promote the polarization of macrophages to the M2 phenotype, thereby inhibiting the development of schistosomiasis. In comparison to the rIL-37 protein, the CPP-IgG2Fc-IL-37 protein has the advantages of being effective in small doses and having fewer side effects and a better efficacy.

A Malicious Domain Detection Model Based on Improved Deep Learning.

With the rapid development of the Internet, malicious domain names pose more and more serious threats to many fields, such as network security and social security, and there have been many research results on malicious domain detection. This article proposes a malicious domain name detection model based on improved deep learning, which can combine the advantages of three different network models, convolutional neural network (CNN), temporal convolutional network (TCN), and long short-term memory network (LSTM) in malicious domain name detection, to obtain a better detection effect than that of the original single or two models. Experiments show that the effect of the improved deep learning model proposed in this article is better than that of the combined model of CNN and LSTM or the combined model of CNN and TCN, and the accuracy and regression rates reached 99.76% and 98.81%, respectively.

CD97 promotes spleen dendritic cell homeostasis through the mechanosensing of red blood cells.

Dendritic cells (DCs) are crucial for initiating adaptive immune responses. However, the factors that control DC positioning and homeostasis are incompletely understood. We found that type-2 conventional DCs (cDC2s) in the spleen depend on Gα13 and adhesion G protein-coupled receptor family member-E5 (Adgre5, or CD97) for positioning in blood-exposed locations. CD97 function required its autoproteolytic cleavage. CD55 is a CD97 ligand, and cDC2 interaction with CD55-expressing red blood cells (RBCs) under shear stress conditions caused extraction of the regulatory CD97 N-terminal fragment. Deficiency in CD55-CD97 signaling led to loss of splenic cDC2s into the circulation and defective lymphocyte responses to blood-borne antigens. Thus, CD97 mechanosensing of RBCs establishes a migration and gene expression program that optimizes the antigen capture and presentation functions of splenic cDC2s.

A digital twin auxiliary approach based on adaptive sparse attention network for diesel engine fault diagnosis.

Condition monitoring and fault diagnosis of diesel engines are of great significance for safety production and maintenance cost control. The digital twin method based on data-driven and physical model fusion has attracted more and more attention. However, the existing methods lack deeper integration and optimization facing complex physical systems. Most of the algorithms based on deep learning transform the data into the substitution of the physical model. The lack of interpretability of the deep learning diagnosis model limits its practical application. The attention mechanism is gradually developed to access interpretability. In this study, a digital twin auxiliary approach based on adaptive sparse attention network for diesel engine fault diagnosis is proposed with considering its signal characteristics of strong angle domain correlation and transient non-stationary, in which a new soft threshold filter is designed to draw more attention to multi decentralized local fault information dynamically in real time. Based on this attention mechanism, the distribution of fault information in the original signal can be better visualized to help explain the fault mechanism. The valve failure experiment on a diesel engine test rig is conducted, of which the results show that the proposed adaptive sparse attention mechanism model has better training efficiency and clearer interpretability on the premise of maintaining performance.

Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury.

Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While NK cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell-deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.

CircHIPK3 Facilitates the G2/M Transition in Prostate Cancer Cells by Sponging miR-338-3p.

BACKGROUND: Circular RNAs (circRNAs) play a crucial role in gene expression regulation. CircHIPK3 is a circRNA derived from Exon 2 of HIPK3 gene and its role in prostate cancer (PCa) is still unclear. METHODS: CCK8 assays, flow cytometry and colony formation assays were performed to assess the effects of circHIPK3 in PCa cells. Bioinformatics analysis, RNA pull-down assay, RNA immunoprecipitation assay (RIP), and luciferase activity assay were performed to dissect the mechanism underlying circHIPK3-mediated G2/M transition in PCa cells. RESULTS: CircHIPK3 expression was upregulated in PCa cells and prostate cancer tissues. Overexpression of circHIPK3 or circHIPK3 silencing altered PCa viability, proliferation and apoptosis in vitro. CircHIPK3 could sponge miR-338-3p and inhibit its activity, resulting in increased expression of Cdc25B and Cdc2 in vitro. CONCLUSION: CircHIPK3 promotes G2/M transition and induces PCa cell proliferation by sponging miR-338-3p and increasing the expression of Cdc25B and Cdc2. CircHIPK3 may play an oncogenic role in PCa.

PLCε knockdown prevents serine/glycine metabolism and proliferation of prostate cancer by suppressing YAP.

The metabolic reprogramming is an important basis for the development of many tumors, including prostate cancer (PCa). Metabolic changes in many amino acids consist of serine and glycine affect the biological behavior of them. Phospholipase C epsilon (PLCε) plays an important role as an oncogene. However, its role in regulating amino acid metabolism remains unclear. In this study, results found significantly positive correlation between PLCε and Yes-associated protein (YAP) in PCa tissues. LC-MS/MS and GC-MS results further displayed abnormally elevated levels of serine, glycine and its some downstream metabolites in the blood of PCa patients. Secondly, PLCε knockdown can inhibit serine/glycine producing and proliferation of PCa both in vivo and in vitro. Mechanistically, PLCε may affect the serine/glycine metabolism by regulating dephosphorylation and nuclear translocation of YAP. More interestingly, verteporfin (VP, a specific inhibitor of YAP) could effectively enhance the PLCε-depletion induced inhibition of serine/glycine secretion and growth. Overall, this research revealed the possibility of anomalous serine/glycine levels in the blood for the diagnosis of PCa, identified the important role of the PLCε/YAP axis in regulating serine/glycine metabolism, cell proliferation and tumor growth, and suggested the combination of VP with PLCε-depletion may provide a new idea for the treatment of PCa.

Mitochondrial DNA Stimulates TLR9-Dependent Neutrophil Extracellular Trap Formation in Primary Graft Dysfunction.

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.

An Efficient Schistosoma japonicum Bivalent Membrane Protein Antigen DNA Vaccine Against Schistosomiasis in Mice.

BACKGROUND Schistosomiasis is one of the most important infectious parasitic diseases in the world. The most important was to control schistosomiasis is through a combination of medical therapy and immunization. The membrane antigens Tsp2 and 29 from Schistosoma are promising anti-schistosomiasis vaccine candidates. MATERIAL AND METHODS In this study, the pcDNA3.1(+)-SjTsp2, pcDNA3.1(+)-Sj29, and pcDNA3.1 (+)-SjTsp2-29 eukaryotic expression vectors were successfully constructed as DNA vaccines, and the protective abilities of these vaccines were evaluated in mice. RESULTS The results showed that vaccination with SjTsp2, Sj29, and SjTsp2-29 reduced parasite burden and hepatic pathology compared to the control group, and the protective effect of the bivalent SjTsp2-29 DNA vaccine was better than that of the univalent SjTsp2 or Sj29 DNA vaccines. We also found high levels of IgG, IgG1, and IgG2a against SjTsp2, Sj29, and SjTsp2-29 DNA vaccines, with high expression of IFN-γ and no IL-4 in the mice. CONCLUSIONS The double-membrane antigen DNA vaccine SjTsp2-29 elicited protection against Schistosoma infection and might serve as a vaccine candidate.

Potential role of IL-37 signaling pathway in feedback regulation of autoimmune Hashimoto thyroiditis.

IL-37, the anti-inflammatory cytokine of the IL-1 family, plays several key roles in the regulation of autoimmune diseases. Yet, its role in Hashimoto's thyroiditis (HT) is not clear. In the present study, we found that, in tissues from HT patients, most of the follicular epithelial cells were positive for both IL-37 and single Ig IL-1-related receptor (SIGIRR) by immunohistochemical staining, while the infiltrating lymphocytes and other inflammatory cells hardly expressed any. Meanwhile, mRNA expression levels of IL-37 in peripheral blood mononuclear cells (PBMC) of HT patients were significantly higher than those in normal controls measured by quantitative real-time PCR. Finally, we studied the possible role of IL-37 in IFN-γ-stimulated rat FRTL-5 cells. The results showed that IL-1ß, TNF-α, and MCP-1 mRNA levels were significantly decreased, while the expression of IL-4 mRNA was dramatically up-regulated in IFN-γ-stimulated rat thyroid cell line FRTL-5 pre-treated with IL-37. The current study, for the first time, demonstrated that the IL-37 network is involved in Hashimoto's thyroiditis, and IL-37 signaling pathway may ameliorate the excessive autoimmune responses in this chronic lymphocytic thyroiditis.

Differential gene expression, including Sjfs800, in Schistosoma japonicum females at pre-pairing, initial pairing and oviposition.

BACKGROUND: Schistosomiasis is a prevalent but neglected tropical disease caused by parasitic trematodes of the genus Schistosoma, with the primary disease-causing species being S. haematobium, S. mansoni and S. japonicum. Male-female pairing of schistosomes is necessary for sexual maturity and the production of a large number of eggs, which are primarily responsible for schistosomiasis dissemination and pathology. METHODS: Here, we used microarray hybridization, bioinformatics, quantitative PCR, in situ hybridization and gene silencing assays to identify genes that play critical roles in S. japonicum reproduction biology, particularly in vitellarium development, a process that affects male-female pairing, sexual maturation and subsequent egg production. RESULTS: Microarray hybridization analyses generated a comprehensive set of genes differentially transcribed before and after male-female pairing. Although the transcript profiles of females were similar 16 and 18 days after host infection, marked gene expression changes were observed at 24 days. The 30 most abundantly transcribed genes on day 24 included those associated with vitellarium development. Among these, the gene for female-specific 800 (fs800) was substantially upregulated. Our in situ hybridization results in female S. japonicum indicated that Sjfs800 mRNA was observed only in the vitellarium, localized in mature vitelline cells. Knocking down the Sjfs800 gene in female S. japonicum by approximately 60% reduced the number of mature vitelline cells, decreased rates of pairing and oviposition, and decreased the number of eggs produced in each male-female pairing by about 50%. CONCLUSIONS: These results indicate that Sjfs800 may play a role in vitellarium development and egg production in S. japonicum and suggest that Sjfs800 regulation may provide a novel approach for the prevention or treatment of schistosomiasis.

Functions of the Vasa gene in Schistosoma japonicum as assessed by RNA interference.

Vasa, an enzyme belonging to the helicase family, contributes to the regulation of reproductive system development in many species. Thus, we hypothesized that the Vasa3 gene may function in the reproductive system of the parasite Schistosoma japonicum (S. japonicum), which is a major causative agent of schistosomiasis. It is a severe disease globally affecting humans and animals. To test this hypothesis, we firstly conducted whole mount in situ hybridization analyses and found that the S. japonicum Vasa3 (SjVasa3) gene was expressed mainly in the reproductive organs. We then explored the reproductive functions of Vasa3 in S. japonicum using RNA interference (RNAi) techniques. Coupled schistosomes collected from mice 28days post infection (dpi) were transfected three times with SjVasa3-specific small interfering RNA (siRNA) and cultured in vitro for up to 10days. As measured by quantitative PCR (qPCR) and Western blot analysis, levels of SjVasa3 mRNA and protein in Vasa siRNA treated worms were significantly reduced compared with untreated and scrambled siRNA treated worms. Confocal laser scanning microscopy (CLSM) images showed markedly siRNA induced changes in the morphology of the reproductive organs, especially in the female ovary, vitellarium and the male testes. SjVasa3 gene silencing also significantly reduced egg production. These data demonstrate that SjVasa3 is essential in reproductive organ development and egg production in S. japonicum, and could be a potential target for developing novel compounds to treat schistosomiasis.

Tyrosine kinase 4 is involved in the reproduction of the platyhelminth parasite Schistosoma japonicum.

BACKGROUND: Schistosomiasis is one of the most common parasitic diseases affecting millions of humans and animals worldwide. Understanding the signal transduction pathways and the molecular basis of reproductive regulation in schistosomes is critically important for developing new strategies for preventing and treating these infections. Syk kinases regulate the proliferation, differentiation, morphogenesis, and survival of various types of cells and have been identified in invertebrates. Tyrosine kinase 4 (TK4), a member of the Syk kinase family, plays a pivotal role in gametogenesis in S. mansoni, affecting the development of the testis and ovaries in this parasite. The role of TK4, however, in the reproduction of S. japonicum is poorly understood. METHODS: Here, the complete coding sequence of TK4 gene in S. japonicum (SjTK4) was cloned and characterized. The expression of SjTK4 was analyzed at different life-cycle stages and in various tissues of S. japonicum by qPCR. Piceatannol, a Syk kinase inhibitor, was applied to S. japonicum in vitro. The piceatannol-induced morphological changes of the parasites were observed using confocal laser scanning microscopy and the alterations in important egg-shell synthesis-related genes were examined using qPCR analyses. RESULTS: SjTK4 mRNA was differentially expressed throughout the life-cycle of S. japonicum. SjTK4 mRNA was highly expressed in the ovary and testis of S. japonicum, with the level of gene expression significantly higher in males than in females. The expression levels of some important egg-shell synthesis related genes were higher in the piceatannol-treated groups than in the vehicle-treated control group and the number of eggs and germ cells also decreased in a concentration-dependent manner. Importantly, large pore-like structures can be found in the testis and ovaries of males and females after treating with piceatannol. CONCLUSION: The results suggest that SjTK4 may play an important role in regulating gametogenesis of S. japonicum. The findings may help better understand the fundamental biology of S. japonicum. Moreover, the effect of S. japonicum treatment by piceatannol provides us with a new idea that inhibition of SjTK4 signaling pathway can effectively retard the development of the testis and ovaries.

Development of monoclonal antibodies against Sj29 and its possible application for schistosomiasis diagnosis.

OBJECTIVE: Timely Schistosoma japonicum detection improves outcomes in schistosomiasis. Here, we established a double antibody sandwich ELISA to detect Schistosoma japonicum. METHODS: Sj29 polyclonal and monoclonal antibodies were developed and identified. A Sj29 double antibody sandwich ELISA was evaluated. RESULTS: Assay sensitivity for detecting Schistosoma japonicum circulating antigen Sj29 was 76.7% (23/30), 54.5% (18/33) and 50.0% (18/36) in patients with acute, chronic and advanced schistosomiasis. No false positives or cross-reactivity was observed in healthy controls or patients with clonorchiasis, paragonimiasis, or ancylostomiasis, respectively. By contrast, false positives (5.7%) and cross-reactivity (6.5%-10%) were detected using an AWA-ELISA. The circulating antigen positive rates decreased significantly faster than that of the antibody detection after 6 months treatment (22.2%, 4/18 and 88.9%, 16/18). Chi-Square Tests revealed that Sj29 sandwich ELISA had lower sensitivity than AWA indirect ELISA in the detection of S. japonicum infected patients (p<0.05). Although our assay detection specificity in patients infected with other parasites or healthy controls appeared higher, the difference between the assays was insignificant. However, our assay showed significantly better results in monitoring praziquantel therapeutic effects (p=0.001), with antigen-positive rates decreasing significantly faster than antibody detection rates after 6 months of treatment (22.2%, 4/18 versus 88.9%, 16/18). CONCLUSIONS: Sj29 double antibody sandwich ELISA was established. The specificity of this method for detecting healthy sera was 100%. Meanwhile, Sj29 sandwich ELISA may have a potential diagnostic capability to distinguish current from past infections and assess drug treatment responses.

Function of Nanos1 gene in the development of reproductive organs of Schistosoma japonicum.

Nanos is a necessary factor in the differentiation and migration of primordial germ cells. It is closely associated with the development of genitalia in a wide range of species. We questioned whether Nanos was involved in the reproductive organ development of Schistosoma japonicum. Firstly, by in situ hybridization, S. japonicum Nanos1 (SjNanos1) gene was expressed mainly in reproductive organs of S. japonicum. Then, the paired schistosome of 28 days post-infection (dpi) was transfected with SjNanos1 small interfering RNA three times and cultured in vitro for 10 days. SjNanos1 expression suppression in the mRNA and protein levels were confirmed compared to that of the controls. The morphological changes in reproductive organs and egg production were observed after SjNanos1 gene knockdown. The results observed by confocal laser scanning microscopy showed significant changes in the morphology of reproductive organs of parasites, especially the female ovaries, vitellarium, and the male testes, after RNAi. In addition, SjNanos1 silencing also induced the reduction of eggs, and affected the changes of reproduction-related genes, like Pumilio, CNOT6L, and Fs800. Therefore, our findings demonstrate that the SjNanos1 gene is essential in the development of reproductive organs and the egg production of S. japonicum.

The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors.

Platelets are critical for haemostasis, thrombosis, and inflammatory responses, but the events that lead to mature platelet production remain incompletely understood. The bone marrow has been proposed to be a major site of platelet production, although there is indirect evidence that the lungs might also contribute to platelet biogenesis. Here, by directly imaging the lung microcirculation in mice, we show that a large number of megakaryocytes circulate through the lungs, where they dynamically release platelets. Megakaryocytes that release platelets in the lungs originate from extrapulmonary sites such as the bone marrow; we observed large megakaryocytes migrating out of the bone marrow space. The contribution of the lungs to platelet biogenesis is substantial, accounting for approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature megakaryocytes along with haematopoietic progenitors in the extravascular spaces of the lungs. Under conditions of thrombocytopenia and relative stem cell deficiency in the bone marrow, these progenitors can migrate out of the lungs, repopulate the bone marrow, completely reconstitute blood platelet counts, and contribute to multiple haematopoietic lineages. These results identify the lungs as a primary site of terminal platelet production and an organ with considerable haematopoietic potential.

Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation.

RATIONALE: Primary graft dysfunction (PGD) causes early mortality after lung transplantation and may contribute to late graft failure. No effective treatments exist. The pathogenesis of PGD is unclear, although both neutrophils and activated platelets have been implicated. We hypothesized that neutrophil extracellular traps (NETs) contribute to lung injury in PGD in a platelet-dependent manner. OBJECTIVES: To study NETs in experimental models of PGD and in lung transplant patients. METHODS: Two experimental murine PGD models were studied: hilar clamp and orthotopic lung transplantation after prolonged cold ischemia (OLT-PCI). NETs were assessed by immunofluorescence microscopy and ELISA. Platelet activation was inhibited with aspirin, and NETs were disrupted with DNaseI. NETs were also measured in bronchoalveolar lavage fluid and plasma from lung transplant patients with and without PGD. MEASUREMENTS AND MAIN RESULTS: NETs were increased after either hilar clamp or OLT-PCI compared with surgical control subjects. Activation and intrapulmonary accumulation of platelets were increased in OLT-PCI, and platelet inhibition reduced NETs and lung injury, and improved oxygenation. Disruption of NETs by intrabronchial administration of DNaseI also reduced lung injury and improved oxygenation. In bronchoalveolar lavage fluid from human lung transplant recipients, NETs were more abundant in patients with PGD. CONCLUSIONS: NETs accumulate in the lung in both experimental and clinical PGD. In experimental PGD, NET formation is platelet-dependent, and disruption of NETs with DNaseI reduces lung injury. These data are the first description of a pathogenic role for NETs in solid organ transplantation and suggest that NETs are a promising therapeutic target in PGD.