Terahertz Time-Domain Spectroscopic Characteristics of Typical Metallic Minerals.

Accurate identification and understanding of various metallic minerals are crucial for deciphering geological formations, structures, and ages. Giving their pivotal role as essential natural resources, a microscopic exploration of metallic minerals becomes imperative. Traditional analytical methods, while helpful, exhibit certain limitations. However, terahertz time-domain spectroscopy, distinguished by its high signal-to-noise ratio, expansive frequency band, and low incident wave energy, is a promising complement to conventional techniques in characterizing metallic minerals. This study employs terahertz time-domain spectroscopy to examine samples of Stibnite, Sphalerite, Galena, and Pyrite originating from diverse geological conditions. The vibrations of molecules within these metallic minerals induce discernible changes in the terahertz spectra. Our findings untiate the extensive potential of terahertz time-domain spectroscopy in the characterization of metallic minerals, affirming its considerable practical value in mineral resource exploration.

LSD1: an emerging face in altering the tumor microenvironment and enhancing immune checkpoint therapy.

Dysregulation of various cells in the tumor microenvironment (TME) causes immunosuppressive functions and aggressive tumor growth. In combination with immune checkpoint blockade (ICB), epigenetic modification-targeted drugs are emerging as attractive cancer treatments. Lysine-specific demethylase 1 (LSD1) is a protein that modifies histone and non-histone proteins and is known to influence a wide variety of physiological processes. The dysfunction of LSD1 contributes to poor prognosis, poor patient survival, drug resistance, immunosuppression, etc., making it a potential epigenetic target for cancer therapy. This review examines how LSD1 modulates different cell behavior in TME and emphasizes the potential use of LSD1 inhibitors in combination with ICB therapy for future cancer research studies.

The role of lncRNAs and exosomal lncRNAs in cancer metastasis.

Tumor metastasis is the main reason for cancer-related death, but there is still a lack of effective therapeutic to inhibit tumor metastasis. Therefore, the discovery and study of new tumor metastasis regulators is a prominent measure for cancer diagnosis and treatment. Long non-coding RNA (lncRNA) is a type of non-coding RNAs over 200 bp in length. It has been shown that the abnormally expressed lncRNAs promote tumor metastasis by participating in the epithelial-to-mesenchymal transition (EMT) process, altering the metastatic tumor microenvironment, or changing the extracellular matrix. It is,thus, critical to explore the regulation of lncRNAs expression in cells and the molecular mechanism of lncRNA-mediated cancer metastasis. Simultaneously, it has been shown that lncRNA is one kind of the main components of exosomes, which protects lncRNAs from being rapidly degraded. Meanwhile, the components of exosomes are parent-specific, making exosomal lncRNAs to be potential tumor metastasis markers and therapeutic targets. In view of this, we also summarized the aberrant enrichment of lncRNAs in exosomes and their role in metastatic cancer. The aberrant lncRNAs and exosomal lncRNAs gradually become biomarkers and therapeutic targets for tumor metastatic, and the potential of lncRNAs in therapeutics are studied here. Besides, the lncRNA-related databases, which could greatly facilitate in the study of lncRNAs and exosomal lncRNAs in metastatic of cancer are included in this review.

Molecular Determinants of Species Specificity of α-Conotoxin TxIB towards Rat and Human α6/α3ß4 Nicotinic Acetylcholine Receptors.

Conotoxins are widely distributed and important for studying ligand-gated ion channels. TxIB, a conotoxin consisting of 16 amino acids derived from Conus textile, is a unique selective ligand that blocks rat α6/α3ß2ß3 nAChR (IC50 = 28 nM) without affecting other rat subtypes. However, when the activity of TxIB against human nAChRs was examined, it was unexpectedly found that TxIB had a significant blocking effect on not only human α6/α3ß2ß3 nAChR but also human α6/α3ß4 nAChR, with an IC50 of 537 nM. To investigate the molecular mechanism of this species specificity and to establish a theoretical basis for drug development studies of TxIB and its analogs, different amino acid residues between human and rat α6/α3 and ß4 nAChR subunits were identified. Each residue of the human species was then substituted with the corresponding residue of the rat species via PCR-directed mutagenesis. The potencies of TxIB towards the native α6/α3ß4 nAChRs and their mutants were evaluated through electrophysiological experiments. The results showed that the IC50 of TxIB against h[α6V32L, K61R/α3]ß4L107V, V115I was 22.5 µM, a 42-fold decrease in potency compared to the native hα6/α3ß4 nAChR. Val-32 and Lys-61 in the human α6/α3 subunit and Leu-107 and Val-115 in the human ß4 subunit, together, were found to determine the species differences in the α6/α3ß4 nAChR. These results also demonstrate that the effects of species differences between humans and rats should be fully considered when evaluating the efficacy of drug candidates targeting nAChRs in rodent models.

Acute kidney injury in cancer patients.

OBJECTIVE: We want to know the causes of AKI in oncology patients, including disease-related complications and the nephrotoxicity of chemotherapy drugs, in order to provide more useful clinical information. METHODS: In this review, an electronic search of the English language literature was performed in the database PubMed, with the results enriched by manual searches and citation mining, factors investigated in the selected articles included acute kidney injury, oncology, chemotherapy, anticancer drug, antitumor drug. RESULTS: According to the searched articles, we summarized the causes (including pre-renal, intrinsic renal, and post-renal lesion) of AKI in cancer patients and the corresponding management measures. Among the pre-renal factors we mainly described hypercalcemia, hematopoietic cell transplantation, post-renal factors we mainly described hemorrhagic cystitis, and intrinsic renal factors we mainly described thrombotic microangiopathy, chemotherapeutics, tumor lysis syndrome, cast nephropathy, in which the emphasis was on chemotherapy drug associated AKI and its treatment. CONCLUSIONS: AKI is not uncommon in cancer patients, and has diverse causes and negative outcomes. Both nephrologists and oncologists need to be aware of the unique reasons of AKI in this population and its optimal management.

Immunosuppressive activity of a cycloartane triterpene glycoside from Beesia calthaefolia by inhibiting T cell proliferation.

BC-1 is a cycloartane triterpene glycoside isolated from the whole plant of Beesia calthaefolia. Our recent studies proved that BC-1 inhibited proliferation of splenic lymphocyte and phagocytosis of macrophages, and inhibited the increased production of TNF-α and IL-1ß. However, it lacks of study about the immunomodulatory effect of BC-1 on purified T lymphocytes. Therefore, in the present study, we evaluated the suppressive potentials of BC-1 on immune responses in vitro. BC-1 markedly suppressed anti-CD3/CD28 mAbs (mAbs) induced murine T lymphocytes proliferation, the expression levels of CD69 and CD25 of CD3+ T cells. BC-1 could strongly decrease ratio of CD4+/CD8+, decrease the Th1/Th2 cytokines production (IL-2, IFN-γ, IL-4, and IL-10) of CD4+ T-cells. In addition, we studied signal transduction pathways about T-cell activation on puried murine CD4+ T lymphocytes by western-blot assay. The data revealed that BC-1 could inhibit the activation of JNK, ERK and PI3K/AKT signal transduction pathways. These results indicated that BC-1 possesses potential downregulating effect on the immune system and might be developed as an immunosuppressive agent in treatment of CD4+ T cell-mediated inflammatory and undesired immune responses.

Silicon, an important exposure marker in vivo in silicosis research.

PURPOSE: The degree of silicosis exposure is closely related to the progress of silicosis. At present, we use animal and human studies to explore whether silicon can be an important exposure marker in the development of silicosis. METHODS: Rats were randomly divided into 2 groups: (1) controls; and (2) silicosis. Rats in the silicosis group were killed at 4, 8, 12, 16, 24 h, 3, 7, 14, 21, and 28 days. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) were performed to observe the histomorphology of lung tissue. The expression levels of CC16 and SP-D were detected using ELISA kits. In addition, we conducted a population study. Workers who have been selected to work in an iron mine for more than 1 year as research objects. The population was divided into four groups: silicosis exposure group (workers exposed to silica dust for more than 1 year in an iron mine were selected); patients group (silicosis patients); observation group (evidence of disease not meeting formal diagnostic criteria) and control group. Both the levels of trace silicon in the urine and blood of rats and human subjects were measured with ICP-MS. RESULTS: Serum levels of silicon were immediately increased in rats exposed to silicon dust. Similarly, our population study revealed that the silicon level in the silica exposure group and the observing group (exposed but no obvious symptoms) were significantly increased over that of the control group (P < 0.05). In subjects with extended exposure to silica, the serum and urine silicon level in exposed workers appeared to rapidly increase, reaching its peak in 1-5 years, followed by a gradual decline thereafter. Workers exposed to dust for less than 10 years were divided into subgroups by 2-year limit. The levels of serum silicon, urine silicon, TGF-ß1, and TNF-α were significantly higher than that of control group. CONCLUSION: Changes of the serum levels of silicon occurred earlier than the expression of cytokines such as TNF-α, TGF-ß1, CC16, and SP-D. The level of silicon in workers rapidly increased after exposure to silica, and the change occurred before the expression of TGF-ß1 and TNF-α. As a whole, the findings suggest that determining the level of silicon in vivo might be an effective exposure marker in the diagnosis and pathogenesis of silicosis.

Histone H4 aggravates inflammatory injury through TLR4 in chlorine gas-induced acute respiratory distress syndrome.

BACKGROUND: Chlorine gas (Cl2) exposure remains a public health concern in household, occupational, and transportation accidents around the world. The death rate associated with acute respiratory distress syndrome (ARDS) caused by high concentrations of Cl2 is very high, mainly because the pathogenesis of ARDS remains unclear. Histone H4 has been identified as an important endogenous pro-inflammatory molecule. The present study aimed to examine the pathogenic role of histone H4 in Cl2-induced ARDS. METHODS: ARDS was induced by Cl2 exposure in male C57BL/6 mice. Circulating histone H4, blood gas, pulmonary edema, endothelial activation, and neutrophil infiltration were measured during acute lung injury (ALI). Histone H4 or anti-H4 antibody was administered through the tail vein 1 h prior to Cl2 exposure to study the pathogenic role of histone H4. Toll-like receptor 2 knock-out (Tlr2-KO) and Tlr4-KO mice were used in conjunction with blocking antibody against TLR1, TLR2, TLR4, or TLR6 to explore the mechanism involved in histone H4-mediated injury. RESULTS: Cl2 exposure induced a concentration-dependent ALI. The levels of circulating histone H4 were positively correlated with Cl2 concentrations. Pretreatment with intravenous histone H4 further aggravated lethality rate, blood gas, endothelial activation, and neutrophil infiltration, while anti-H4 antibody showed protective effects. Tlr4 deficiency improved lethality rate, blood gas, and pulmonary edema, and prevented endothelial and neutrophil activation caused by Cl2 exposure. More importantly, Tlr4 gene deletion greatly diminished the effect of histone H4 or anti-H4 antibody observed in wild-type (WT) mice. The impact of Tlr2 on inflammatory injury was not significant. The role of TLRs was also validated by endothelial activation mediated by histone H4 in vitro. CONCLUSIONS: Circulating histone H4 played a pro-inflammatory role in ARDS caused by Cl2. TLR4 was closely involved in histone H4-mediated inflammatory injury. Therefore, intervention targeting histone H4 is potentially protective.

Extracellular Histones Promote Pulmonary Fibrosis in Patients With Coal Workers' Pneumoconiosis.

OBJECTIVE: This investigation assessed the profibrotic role that extracellular histones play in the pathogenesis of coal workers' pneumoconiosis (CWP). METHODS: The correlation of extracellular histones with small opacity profusion (SOP) and transforming growth factor-ß (TGF-ß) was analyzed. The stimulating effect of extracellular histones on pulmonary fibroblast was assessed in vitro. RESULTS: The levels of extracellular histones in plasma were positively correlated with SOP and TGF-ß in the coal miners investigated. Plasma collected from patients with CWP caused apparent lung fibroblast proliferation, while anti-H4 antibody antagonized the stimulating effect of the patient plasma by blocking histone H4. In vitro experiments showed that extracellular histones directly stimulated fibroblast proliferation. CONCLUSION: Consistent with our hypothesis, the concentrations of extracellular histones were indices of the severity of pulmonary fibrosis in simple CWP, and extracellular histones-targeted intervention could inhibit the proliferation of lung fibroblast.

Rational Engineering a Multichannel Upconversion Sensor for Multiplex Detection of Matrix Metalloproteinase Activities.

Optical sensing of cancer-relevant protease is of great value for cancer diagnostics, prognosis, and drug discovery. Multiplex sensing is known to improve predicative accuracy yet remains challenging because of severe fluorescence signal crosstalk in a single assay. Herein, we developed a multichannel optical sensor based on upconversion nanoparticles for multiplex ratiometric sensing of proteolytic activities of two matrix metalloproteinases (MMP-2 and MMP-7). To this end, we rationally designed a NaYF4:Gd3+/Yb3+@NaYF4:Yb3+/Tm3+/Er3+ core-shell structure that favors multicolor narrow-band emission of both Tm3+ and Er3+ dopants and efficient luminescence resonance energy transfer (LRET) between the dopants in the shell and the fluorophores on the particle surface. The sensor was constructed via a facile phase transfer protocol using two polyhistidine-containing peptides conjugated with different fluorophores (FITC and TAMRA) as coligands. The blue and green emission could be specifically activated by MMP-7 and MMP-2, respectively, upon peptide cleavage, and the red emission could serve as an internal reference for ratiometric sensing. The sensor exhibits high specificity and sensitivity toward both targets with little signal crosstalk and cross-reactivity. It could potentially serve as a general platform for multiplex detection of various types of proteases.

Pulmonary endothelial activation caused by extracellular histones contributes to neutrophil activation in acute respiratory distress syndrome.

BACKGROUND: During the acute respiratory distress syndrome (ARDS), neutrophils play a central role in the pathogenesis, and their activation requires interaction with the endothelium. Extracellular histones have been recognized as pivotal inflammatory mediators. This study was to investigate the role of pulmonary endothelial activation during the extracellular histone-induced inflammatory response in ARDS. METHODS: ARDS was induced in male C57BL/6 mice by intravenous injection with lipopolysaccharide (LPS) or exogenous histones. Concurrent with LPS administration, anti-histone H4 antibody (anti-H4) or non-specific IgG was administered to study the role of extracellular histones. The circulating von Willebrand factor (vWF) and soluble thrombomodulin (sTM) were measured with ELISA kits at the preset time points. Myeloperoxidase (MPO) activity in lung tissue was measured with a MPO detection kit. The translocation of P-selectin and neutrophil infiltration were measured by immunohistochemical detection. For in vitro studies, histone H4 in the supernatant of mouse lung vascular endothelial cells (MLVECs) was measured by Western blot. The binding of extracellular histones with endothelial membrane was examined by confocal laser microscopy. Endothelial P-selectin translocation was measured by cell surface ELISA. Adhesion of neutrophils to MLVECs was assessed with a color video digital camera. RESULTS: The results showed that during LPS-induced ARDS extracellular histones caused endothelial and neutrophil activation, as seen by P-selectin translocation, release of vWF, an increase of circulating sTM, lung neutrophil infiltration and increased MPO activity. Extracellular histones directly bound and activated MLVECs in a dose-dependent manner. On the contrary, the direct stimulatory effect of exogenous histones on neutrophils was very limited, as measured by neutrophil adhesion and MPO activity. With the contribution of activated endothelium, extracellular histones could effectively activating neutrophils. Both inhibiting the endothelial activation with an anti-toll like receptor (TLR) antibody and inhibiting the interaction of the endothelium with neutrophil using an anti-P-selectin antibody decreased the degree of neutrophil activation. CONCLUSIONS: Extracellular histones are pro-inflammatory mediators in LPS-induced ARDS in mice. In addition to direct action to neutrophils, extracellular histones promote neutrophil adhesion and subsequent activation by first activating the pulmonary endothelium via TLR signaling. Thus, endothelial activation is important for extracellular histone-induced inflammatory injury.

Enhanced expression levels of aquaporin-1 and aquaporin-4 in A549 cells exposed to silicon dioxide.

Aquaporins (AQPs), water channel proteins in the cell membranes of mammals, have been reported to be important in maintaining the water balance of the respiratory system. However, little is known regarding the role of AQP in occupational pulmonary diseases such as silicosis. The present study investigated the expression of AQP1 and AQP4 in the human A549 alveolar epithelial cell line stimulated by silica (SiO2). A549 cells were cultured and divided into four groups: Control, SiO2­stimulated, AQP1 inhibitor and AQP4 inhibitor. The cells of the SiO2­stimulated group were stimulated with SiO2 dispersed suspension (50 mg/ml). The cells of the inhibitor group were pretreated with mercury (II) chloride (HgCl2; a specific channel inhibitor of AQP1) and 2­(nicotinamide)­1,3,4­thiadiazole (TGN­020; a specific channel inhibitor of AQP4) and stimulated with SiO2. The mRNA expression levels of AQP1 and AQP4 were detected by reverse transcription­quantitative polymerase chain reaction, and the protein expression levels of AQP1 and AQP4 were detected by western blotting and immunocytochemistry. Compared with the control group, the expression levels of AQP1 and AQP4 mRNA and protein in SiO2­stimulated groups increased and subsequently decreased (AQP1 peaked at 2 h and AQP4 at 1h; both P<0.001 compared with control group). In the inhibitor group, expression levels were increased compared with controls; however, they were significantly decreased compared with the SiO2­stimulated group at 2 h (AQP1; P<0.001) and 1 h (AQP4; P<0.001). The expression of AQP1 and AQP4 increased when exposed to SiO2, and this was inhibited by HgCl2 and TGN­020, suggesting that AQP1 and AQP4 may contribute to A549 cell damage induced by SiO2. AQP1 and AQP4 may thus be involved in the initiation and development of silicosis.

Cycloartane triterpenes from Beesia calthaefolia and their anticomplement structure-activity relationship study.

Fifteen cycloartane triterpenes were isolated from Beesia calthaefolia and among them one was new cycloartane triterpenoid. The structure of new compound was determined by the application of spectroscopic analyses and chemical methods. The fifteen compounds were evaluated for their anticomplement activity by classic pathway. The structure-activity relationship analysis indicated that the configurations of 12-OH is preferable to be α than ß, and 18-OH can decrease while 15-OH can increase the anticomplement activity, but saponin with both 15-OH and 18-OH lost most of its activity. The glycosyl moiety of most isolated cycloartane triterpenes is xylosyl. When xylosyl was substituted by glucosyl or galactosyl, their anticomplement activities were decreased or increased, respectively. Further structure-activity relationship (SAR) studies must be carried out to achieve general conclusions regarding the effect of further functionalizations on the anticomplement saponins.

[The study on the change of extracellular histones in human plasma during the pathogenesis of silicosis].

OBJECTIVE: To investigate the plasma level of extracellular histones in patients with silicosis, and to explore the role of extracellular histones in the pathogenesis of pulmonary fibrosis in silicosis. METHODS: Sixty-two patients with silicosis were enrolled as the silicosis group, consisting of 23 patients with stage I silicosis, 25 with stage II silicosis, and 14 with stage III silicosis; sixty workers who had a history of occupational exposure to silica dust for more than 2 years and had not been diagnosed with silicosis were enrolled as the silica dust exposure group; sixty-five healthy workers without a history of occupational exposure to dust were enrolled as healthy controls. Enzyme-linked immunosorbent assay was applied to measure the plasma levels of plasma extracellular histone (H4) and transforming growth factor-ß(TGF-ß). RESULTS: Compared with healthy controls [(0.82±0.67) µg/ml], the silica dust exposure group[(4.14±2.85) µg/ml] and silicosis group[(9.50±5.04) µg/ml] had significant increases in plasma level of H4 (P<0.01). The plasma level of H4 was significantly correlated with the stage of silicosis(r=0.8955, P=0.0388). The silicosis group had a significantly higher plasma level of TGF-ß than the silica dust exposure group and healthy controls(P <0.05). In the patients with silicosis, the plasma level of H4 was significantly correlated with that of TGF-ß(r=0.5375, P<0.01). CONCLUSION: The plasma level of extracellular histones increases significantly in the pathogenesis of silicosis, and extracellular histones may play an important role in the progression of fibrosis in silicosis.

Ginsenoside Rg1 enhances lymphatic transport of intrapulmonary silica via VEGF-C/VEGFR-3 signaling in silicotic rats.

Ginsenoside Rg1, extracted mainly from Panax ginseng, has been shown to exert strong pro-angiogenic activities in vivo. But it is unclear whether ginsenoside Rg1 could promote lung lymphangiogenesis to improve lymphatic transport of intrapulmonary silica in silicotic rats. Here we investigated the effect of ginsenoside Rg1 on lymphatic transport of silica during experimental silicosis, and found that ginsenoside Rg1 treatment significantly raised the silicon content in tracheobronchial lymph nodes and serum to reduce the silicon level in lung interstitium, meanwhile increased pulmonary lymphatic vessel density by enhancing the protein and mRNA expressions of vascular endothelial growth factor-C (VEGF-C) and vascular endothelial growth factor receptor-3 (VEGFR-3). The stimulative effect of ginsenoside Rg1 on lymphatic transport of silica was actively correlated with its pro-lymphangiogenic identity. And VEGFR-3 inhibitor SAR131675 blocked these above effects of ginsenoside Rg1. These findings suggest that ginsenoside Rg1 exhibits good protective effect against lung burden of silica during experimental silicosis through improving lymphatic transport of intrapulmonary silica, which is potentially associated with the activation of VEGF-C/VEGFR-3 signaling pathway.

One new cycloartane triterpene glycoside from Beesia calthaefolia.

One new cycloartane triterpene glycoside (1) was isolated from the whole plant of Beesia calthaefolia. Its structure was elucidated on the basis of extensive spectroscopic data analysis. Its inhibitory effect was measured by the classical pathway of the complement system, and compared with those of known related cycloartane glycosides 2 and 3, previously isolated by us from the same plant. Compounds 1 and 2 exhibited inhibitory activity of complement system with IC50 of 395.3 and 214 µM, respectively. The results suggested that OH at C-12, C-18 and C-15 along with the polarity could affect the inhibitory activity.

Decreased Expression of Aquaporin-1 in Lung Tissue of Silicotic Rats.

BACKGROUND: Aquaporin-1 (AQP-1), found in the early 1990s, a water channel protein in the cell membranes of mammals, has been reported to play an important role in water balance of the respiratory system. However, there are a few studies about the role of AQP in occupational pulmonary disease such as silicosis. This study is to explore the information of aquaporin-1 (AQP-1) in the pathogenesis of silicosis by examining AQP expression, distribution, and location in the lung tissue of a silicotic rat model. METHODS: Male Wistar SPF rats were divided randomly into the following 8 groups (n = 8 per group): (1) saline control group: instillation of 1 mL sterile physiological saline; (2) silica groups (ld, 7d, 14d, 28d, 42d, 56d): instillation of a suspension of 50 mg silica dust in a total volume of 1 mL sterile physiological saline; (3) the normal control group without treatment. Immunohistochemistry, immunofluorescence, and western blot were used to detect distribution and expression of AQP-1 in the lung tissue of rats exposed to silica. RESULTS: The expression of AQP-1 between normal and the saline control rats showed no significant difference, but was decreased in the silicotic model rats' lung. CONCLUSIONS: The expression of AQP-1 decreased in silicotic rats, which suggests that AQP-1 may play an important role in the formation of silicosis.

Salvianolic acids attenuate rat hippocampal injury after acute CO poisoning by improving blood flow properties.

Carbon monoxide (CO) poisoning causes the major injury and death due to poisoning worldwide. The most severe damage via CO poisoning is brain injury and mortality. Delayed encephalopathy after acute CO poisoning (DEACMP) occurs in forty percent of the survivors of acute CO exposure. But the pathological cause for DEACMP is not well understood. And the corresponding therapy is not well developed. In order to investigate the effects of salvianolic acid (SA) on brain injury caused by CO exposure from the view point of hemorheology, we employed a rat model and studied the dynamic of blood changes in the hemorheological and coagulative properties over acute CO exposure. Compared with the groups of CO and 20% mannitol + CO treatments, the severe hippocampal injury caused by acute CO exposure was prevented by SA treatment. These protective effects were associated with the retaining level of hematocrit (Hct), plasma viscosity, fibrinogen, whole blood viscosities and malondialdehyde (MDA) levels in red blood cells (RBCs). These results indicated that SA treatment could significantly improve the deformation of erythrocytes and prevent the damage caused by CO poisoning. Meanwhile, hemorheological indexes are good indicators for monitoring the pathological dynamic after acute CO poisoning.

Extracellular histones play an inflammatory role in acid aspiration-induced acute respiratory distress syndrome.

BACKGROUND: Systemic inflammation is a key feature in acid aspiration-induced acute respiratory distress syndrome (ARDS), but the factors that trigger inflammation are unclear. The authors hypothesize that extracellular histones, a newly identified inflammatory mediator, play important roles in the pathogenesis of ARDS. METHODS: The authors used a hydrochloric acid aspiration-induced ARDS model to investigate whether extracellular histones are pathogenic and whether targeting histones are protective. Exogenous histones and antihistone antibody were administered to mice. Heparin can bind to histones, so the authors studied whether heparin could protect from ARDS using cell and mouse models. Furthermore, the authors analyzed whether extracellular histones are clinically involved in ARDS patients caused by gastric aspiration. RESULTS: Extracellular histones in bronchoalveolar lavage fluid of acid-treated mice were significantly higher (1.832 ± 0.698) at 3 h after injury than in sham-treated group (0.63 ± 0.153; P = 0.0252, n = 5 per group). Elevated histones may originate from damaged lung cells and neutrophil infiltration. Exogenous histones aggravated lung injury, whereas antihistone antibody markedly attenuated the intensity of ARDS. Notably, heparin provided a similar protective effect against ARDS. Analysis of plasma from ARDS patients (n = 21) showed elevated histones were significantly correlated with the degree of ARDS and were higher in nonsurvivors (2.723 ± 0.2933, n = 7) than in survivors (1.725 ± 0.1787, P = 0.006, n = 14). CONCLUSION: Extracellular histones may play a contributory role toward ARDS by promoting tissue damage and systemic inflammation and may become a novel marker reflecting disease activity. Targeting histones by neutralizing antibody or heparin shows potent protective effects, suggesting a potentially therapeutic strategy.

Regulation of silicosis formation by lysophosphatidic acid and its receptors.

Silicosis is a serious occupational disease characterized by lung fibrosis that is caused by long-term inhalation of silica-containing fine particles. Lysophosphatidic acid (LPA) and LPA1/3 plays a role in lung fibrosis. Until recently, there has been little research investigating the role of LPA and LPA receptors (LPAR) in silica-induced development of pulmonary fibrosis. In this study, we evaluated the hypothesis that LPA and LPA1/3 may play a role in silicosis pathogenesis using rat silicosis models induced by intratracheal instillation of silica, and randomly divided into control, silica, and VPC-12249 groups. LPA serum and bronchoalveolar lavage fluid (BALF) levels were quantified by ELISA. α-smooth muscle actin (α-SMA), type I and III collagen protein expression was quantified by western blotting (WB), and type I and III collagen mRNAs detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Lung hydroxyproline (HYP) levels were detected using alkaline hydrolysis, with hematoxylin and eosin (H&E) and picrosirius red staining used for pathological examination. In vitro experiments showed that LPA stimulated fibroblasts proliferated in a time and dose-dependent manner and promoted expression of α-SMA, and type I and III collagen. Moreover, LPA serum and BALF levels increased in silica-instilled rats. In vivo and in vitro experiments revealed that α-SMA expression and collagen deposition reduced significantly after VPC-12249 treatment, and histopathological results show VPC-12249 alleviates silicosis progression. In conclusion, our findings suggest that LPA promotes the proliferation, transformation, and collagen synthesis of fibroblasts, and that LPA-LPA1/3 are involved in the development of silicosis and may serve as novel therapeutic targets for treatment.