Engineered cell and tissue models of pulmonary fibrosis.

The loss of normal alveolar capillary and deregulated angiogenesis occurs simultaneously in idiopathic pulmonary fibrosis (IPF); however the contributions of specific endothelial subpopulations in the development of pulmonary fibrosis are poorly understood. Herein, we perform single-cell RNA sequencing to characterize the heterogeneity of endothelial cells (ECs) in bleomycin (BLM)-induced lung fibrosis in rats. One subpopulation, characterized by the expression of Nos3 and Cav1, is mostly distributed in non-fibrotic lungs and also highly expresses genes related to the "response to mechanical stimulus" and "lung/heart morphogenesis" processes. Another subpopulation of ECs expanded in BLM-treated lungs, characterized by Cxcl12, is observed to be closely related to the pro-fibrotic process in the transcriptome data, such as "regulation of angiogenesis," "collagen binding," and "chemokine activity," and spatially localized to BLM-induced neovascularization. Using CellPhoneDB software, we generated a complex cell-cell interaction network, which predicts the potential roles of EC subpopulations in recruiting monocytes, inducing the proliferation of fibroblasts and promoting the production and remolding of the extracellular matrix (ECM). Taken together, our data demonstrate the high degree of heterogeneity of ECs in fibrotic lung and it is proposed that the interaction between ECs, macrophages, and stromal cells contributes to pathologic IPF.

/pdf/characterization-of-the-heterogeneity-of-endothelial-cells-j3no0xxio4.pdf

Characterization of the heterogeneity of endothelial cells in bleomycin-induced lung fibrosis using single-cell RNA sequencing.

Pulmonary fibrosis (PF) is an interstitial lung disease, in which the exact pathologic mechanisms are not fully understood. Drug trials for the treatment of PF have shown disappointing results and ...

Protective and anti-inflammatory effect of selenium nano-particles against bleomycin-induced pulmonary injury in male rats

In this study, we investigated the effects of nucleolin on lipopolysaccharide (LPS)-induced activation of MAPK and NF-KappaB (NF-κB) signaling pathways and secretion of TNF-α, IL-1β and HMGB1 in THP-1 monocytes. Immunofluorescence assay and Western blotting were used to identify the nucleolin expression in cell membrane, cytoplasm and nucleus of THP-1 monocytes. Inactivation of nucleolin was induced by neutralizing antibody against nucleolin. THP-1 monocytes were pretreated with anti-nucleolin antibody for 1 h prior to LPS challenge. The irrelevant IgG group was used as control. Secretion of inflammatory mediators (TNF-α, IL-1β and HMGB1) and activation of MAPK and NF-κB/I-κB signaling pathways were examined to assess the effects of nucleolin on LPS-mediated inflammatory response. Nucleolin existed in cell membrane, cytoplasm and nucleus of THP-1 monocytes. Pretreatment of anti-nucleolin antibody significantly inhibited the LPS-induced secretion of TNF-α, IL-1β and HMGB1. P38, JNK, ERK and NF-κB subunit p65 inhibitors could significantly inhibit the secretion of IL-1β, TNF-α and HMGB1 induced by LPS. Moreover, the phosphorylation of p38, JNK, ERK and p65 (or nuclear translocation of p65) was significantly increased after LPS challenge. In contrast, pretreatment of anti-nucleolin antibody could significantly inhibit the LPS-induced phosphorylation of p38, JNK, ERK and p65 (or nuclear translocation of p65). However, the irrelevant IgG, as a negative control, had no effect on LPS-induced secretion of TNF-α and IL-1β and phosphorylation of p38, JNK, ERK and p65 (or nuclear translocation of p65). We demonstrated that nucleolin mediated the LPS-induced activation of MAPK and NF-κB signaling pathways, and regulated the secretion of inflammatory mediators (TNF-α, IL-1β and HMGB1).

/pdf/nucleolin-mediates-lps-induced-expression-of-inflammatory-1qo0py4us9.pdf

Nucleolin Mediates LPS-induced Expression of Inflammatory Mediators and Activation of Signaling Pathways.

Inflammation, vascular smooth muscle cell apoptosis and oxidative stress are believed to play important roles in abdominal aortic aneurysm (AAA) pathogenesis. Human kallistatin (KAL; gene SERPINA4) is a serine proteinase inhibitor previously shown to inhibit inflammation, apoptosis and oxidative stress. The aim of this study was to investigate the role of KAL in AAA through studies in experimental mouse models and patients. Serum KAL concentration was negatively associated with the diagnosis and growth of human AAA. Transgenic overexpression of the human KAL gene (KS-Tg) or administration of recombinant human KAL (rhKAL) inhibited AAA in the calcium phosphate (CaPO4) and subcutaneous angiotensin II (AngII) infusion mouse models. Upregulation of KAL in both models resulted in reduction in the severity of aortic elastin degradation, reduced markers of oxidative stress and less vascular smooth muscle apoptosis within the aorta. Administration of rhKAL to vascular smooth muscle cells incubated in the presence of AngII or in human AAA thrombus-conditioned media reduced apoptosis and downregulated markers of oxidative stress. These effects of KAL were associated with upregulation of Sirtuin 1 activity within the aortas of both KS-Tg mice and rodents receiving rhKAL. These results suggest KAL-Sirtuin 1 signalling limits aortic wall remodelling and aneurysm development through reductions in oxidative stress and vascular smooth muscle cell apoptosis. Upregulating KAL may be a novel therapeutic strategy for AAA.

/pdf/kallistatin-limits-abdominal-aortic-aneurysm-by-attenuating-21h8wpa190.pdf

Kallistatin limits abdominal aortic aneurysm by attenuating generation of reactive oxygen species and apoptosis

Kallistatin is a unique serine proteinase inhibitor and heparin-binding protein. A previous study conducted by our group indicated that kallistatin has antiangiogenic and antitumoral activities. In the present study, we report that kallistatin specifically binds to membrane surface-expressed nucleolin with high affinity. Antibody-mediated neutralization or siRNA-induced nucleolin knockdown results in loss of kallistatin suppression of endothelial cell proliferation and migration in vitro and tumor angiogenesis and growth in vivo. In addition, we show that kallistatin is internalized and transported into cell nuclei of endothelial cells via nucleolin. Within the nucleus, kallistatin inhibits the phosphorylation of nucleolin, which is a critical step required for cell proliferation. Thus, we demonstrate that nucleolin is a novel functional receptor of kallistatin that mediates its antiangiogenic and antitumor activities. These findings provide mechanistic insights into the inhibitory effects of kallistatin on endothelial cell growth, tumor cell proliferation, and tumor-related angiogenesis.

/pdf/cell-surface-expression-of-nucleolin-mediates-the-15fge462hi.pdf

Cell surface expression of nucleolin mediates the antiangiogenic and antitumor activities of kallistatin.

The invention discloses a direct fluorescence spectrometric detection method of Adenosine Cyclphosphate in an Adenosine Cyclphosphate injection; the method is as follows: using ultrapure water or redistilled water as a solvent to prepare a plurality of groups of different concentrations of Adenosine Cyclphosphate standard solutions, using a B-R buffer solution to adjust the pH of the standard solutions to 2, heating the standard solutions to 50 DEG C, cooling the standard solutions to room temperature, and placing the standard solutions on a fluorescence spectrophotometer for fluorescence spectroscopy analysis to plot an emission intensity versus Adenosine Cyclphosphate concentration working curve; pipetting a sample to be tested of the Adenosine Cyclphosphate injection, diluting the sample for 10,000 times, and adjusting the pH of the sample solution with the B-R buffer solution to 2, performing fluorescence spectroscopy analysis in a scanning range of 290 nm-550 nm with an excitationwavelength of 285 nm, an excitation slit of 5 nm, and emission slit of 10 nm, determining the the concentration of the Adenosine Cyclphosphate in the sample to be tested by use of the working curve according to the fluorescence emission intensity of the sample to be tested. The detection method has the advantages of good accuracy, low cost, convenient operation and environmental friendliness.

Direct fluorescence spectrometric detection method of Adenosine Cyclphosphate in Adenosine Cyclphosphate injection

Follicle-stimulating hormone (FSH) is the pituitary hormone responsible for testicular tubal development and ovarian follicular recruitment and maturation. Both recombinant and purified urinary FSH are currently used for ovulation induction in women undergoing assisted reproduction. In this report, we describe Chinese hamster ovary (CHO-K1) cell expression of a novel long-acting human FSH single chain analog consisting of the native a and â subunit. A simple but readily scalable column chromatography method was developed to highly purify the recombinant FSH analog. In-vivo bioactivity was evaluated by the ovarian and uterine histopathology examinations. Single SC injection of the recombinant FSH analog (62.5 ig/kg) induced an equivalent increase the number of antral follicle, compared with commercial FSH preparation Folltropin-V (0.5 g/ kg, twice daily for 4 days). The histopathology examination of the ovary and uterus confirmed the efficacy of the FSH analog. These findings indicate that this recombinant FSH analog could serve as a long-acting FSH preparation.

Expression of long-acting human follicle-stimulating hormone analog from Chinese hamster ovary cells and functional characterization

Aberrant angiogenesis and vascular remodeling are the main features of idiopathic pulmonary fibrosis. Kallistatin is an anti-angiogenic peptide with known effects on endothelial cells. This study aimed to demonstrate that kallistatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in a rat model by inhibiting angiogenesis. Twenty-five rats were randomly divided into five experimental groups: (A) Saline only (SA)-as the negative control, (B) BLM only (BLM)-as the model group, (C) BLM and 0.1 mg/kg kallistatin (L-Kal), (D) BLM and 0.5 mg/kg kallistatin (M-Kal), and (E) BLM and 2.5 mg/kg kallistatin (H-Kal). Fibrillar collagen was quantified by Masson's trichrome and hematoxylin-eosin staining. Transforming growth factor-β1 (TGF-β1), α-smooth-muscle-actin (α-SMA) and microvascular density (MVD) were measured by immunohistochemistry. Vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), and tumor necrosis factor-α (TNF-α) were assayed by Western immunoblotting or ELISA. Daily administration of kallistatin attenuated fibrosis in BLM-induced pulmonary fibrosis, as shown by histology. During inflammation from BLM-induced pulmonary fibrosis, kallistatin reduced the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid. Kallistatin also inhibited VEGF expression and phosphorylation of VEGFR2 (Flk-1). In vitro, kallistatin blocked tube formation by inhibiting Flk-1 and GSK-3β phosphorylation. The results demonstrated that continuous administration of kallistatin attenuated BLM-induced pulmonary fibrosis and improved survival of BLM rats. Reducing pulmonary fibrosis was achieved by partial inhibition of pulmonary inflammation and angiogenesis.

Kallistatin protects against bleomycin-induced idiopathic pulmonary fibrosis by inhibiting angiogenesis and inflammation.

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Papers

Cell surface expression of nucleolin mediates the antiangiogenic and antitumor activities of kallistatin.

Direct fluorescence spectrometric detection method of Adenosine Cyclphosphate in Adenosine Cyclphosphate injection

Expression of long-acting human follicle-stimulating hormone analog from Chinese hamster ovary cells and functional characterization

Kallistatin protects against bleomycin-induced idiopathic pulmonary fibrosis by inhibiting angiogenesis and inflammation.