Development and in vitro-in vivo performances of an inhalable indole-3-carboxaldehyde dry powder to target pulmonary inflammation and infection

2021 ◽  
pp. 121004
Author(s):  
Matteo Puccetti ◽  
Larissa Gomes dos Reis ◽  
Marilena Pariano ◽  
Claudio Costantini ◽  
Giorgia Renga ◽  
...  
Keyword(s):  
Pulmonary Inflammation ◽  
Dry Powder

scholarly journals Necroptosis Contributes to Urban Particulate Matter-Induced Airway Epithelial Injury

2018 ◽  
Vol 46 (2) ◽  
pp. 699-712 ◽  
Author(s):  
Feng Xu ◽  
Man Luo ◽  
Lulu He ◽  
Yuan Cao ◽  
Wen Li ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Pulmonary Inflammation ◽  
Periodic Acid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Periodic Acid Schiff ◽  
Mucus Production ◽  
Gm Csf ◽  
Mucin Expression

Background/Aims: Necroptosis, a form of programmed necrosis, is involved in the pathologic process of several kinds of pulmonary diseases. However, the role of necroptosis in particulate matter (PM)–induced pulmonary injury remains unclear. The objective of this study is to investigate the involvement of necroptosis in the pathogenesis of PM-induced toxic effects in pulmonary inflammation and mucus hyperproduction, both in vitro and in vivo. Methods: PM was administered into human bronchial epithelial (HBE) cells or mouse airways, and the inflammatory response and mucus production were assessed. The mRNA expressions of IL6, IL8 and MUC5AC in HBE cells and Cxcl1, Cxcl2, and Gm-csf in the lung tissues were detected by quantitative real-time RT-PCR. The secreted protein levels of IL6 and IL8 in culture supernatants and Cxcl1, Cxcl2, and Gm-csf in bronchoalveolar lavage fluid (BALF) were detected by enzyme-linked immunosorbent assay (ELISA). We used Western blot to measure the protein expressions of necroptosis-related proteins (RIPK1, RIPK3, and Phospho-MLKL), NF-κB (P65 and PP65), AP-1 (P-c-Jun and P-c-Fos) and MUC5AC. Cell necrosis and mitochondrial ROS were detected using flow cytometry. In addition, pathological changes and scoring of lung tissue samples were monitored using hemoxylin and eosin (H&E), periodic acid-schiff (PAS) and immunohistochemistry staining. Results: Our study showed that PM exposure induced RIP and MLKL-dependent necroptosis in HBE cells and in mouse lungs. Managing the necroptosis inhibitor Necrostatin-1 (Nec-1) and GSK’872, specific molecule inhibitors of necroptosis, markedly reduced PM-induced inflammatory cytokines, e.g., IL6 and IL8, and MUC5AC in HBE cells. Similarly, administering Nec-1 significantly reduced airway inflammation and mucus hyperproduction in PM-exposed mice. Mechanistically, we found PM–induced necroptosis was mediated by mitochondrial reactive oxygen species-dependent early growth response gene 1, which ultimately promoted inflammation and mucin expression through nuclear factor κB and activator protein-1 pathways, respectively. Conclusions: Our results demonstrate that necroptosis is involved in the pathogenesis of PM–induced pulmonary inflammation and mucus hyperproduction, and suggests that it may be a novel target for treatment of airway disorders or disease exacerbations with airborne particulate pollution.

Visualization of pulmonary inflammation using noninvasive fluorescence molecular imaging

2008 ◽  
Vol 104 (3) ◽  
pp. 795-802 ◽  
Author(s):  
Jodi Haller ◽  
Damon Hyde ◽  
Nikolaos Deliolanis ◽  
Ruben de Kleine ◽  
Mark Niedre ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Quantitative Imaging ◽  
Pulmonary Inflammation ◽  
Small Animal ◽  
Mouse Lung ◽  
Chronic Obstructive ◽  
Therapy Assessment ◽  
Fluorescence Molecular Imaging

The ability to visualize molecular processes and cellular regulators of complex pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), or adult respiratory distress syndrome (ARDS), would aid in the diagnosis, differentiation, therapy assessment and in small animal-based drug-discovery processes. Herein we report the application of normalized transillumination and fluorescence molecular tomography (FMT) for the noninvasive quantitative imaging of the mouse lung in vivo. We demonstrate the ability to visualize and quantitate pulmonary response in a murine model of LPS-induced airway inflammation. Twenty-four hours prior to imaging, BALB/c female mice were injected via tail vein with 2 nmol of a cathepsin-sensitive activatable fluorescent probe (excitation: 750 nm; emission: 780 nm) and 2 nmol of accompanying intravascular agent (excitation: 674 nm; emission: 694 nm). Six hours later, the mice were anesthetized with isoflurane and administered intranasal LPS in sterile 0.9% saline in 25 μl aliquots (one per nostril). Fluorescence molecular imaging revealed the in vivo profile of cysteine protease activation and vascular distribution within the lung typifying the inflammatory response to LPS insult. Results were correlated with standard in vitro laboratory tests (Western blot, bronchoalveolar lavage or BAL analysis, immunohistochemistry) and revealed good correlation with the underlying activity. We demonstrated the capacity of fluorescence tomography to noninvasively and longitudinally characterize physiological, cellular, and subcellular processes associated with inflammatory disease burden in the lung. The data presented herein serve to further evince fluorescence molecular imaging as a technology highly appropriate for the biomedical laboratory.

scholarly journals GLP-1 Analogue Liraglutide Enhances SP-A Expression in LPS-Induced Acute Lung Injury through the TTF-1 Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Tao Zhu ◽  
Changyi Li ◽  
Xue Zhang ◽  
Chunyan Ye ◽  
Shuo Tang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Pulmonary Inflammation ◽  
Protein A ◽  
Insulin Level ◽  
Underlying Mechanism ◽  
Ultrastructural Changes

The reduction of pulmonary surfactant (PS) is essential for decreased pulmonary compliance and edema in acute lung injury (ALI). Thyroid transcription factor-1 (TTF-1) plays a major role in the regulation of surfactant protein-A (SP-A), the most abundant protein component of PS. Simultaneously, the glucagon-like peptide-1 (GLP-1) analogue can enhance SP-A expression in the lung. However, the underlying mechanism is still unknown. The purpose of this study was to explore whether liraglutide, a GLP-1 analogue, upregulates SP-A expression through the TTF-1 signaling pathway in ALI. In vivo, a murine model of ALI was induced by lipopolysaccharide (LPS). Pulmonary inflammation, edema, insulin level, ultrastructural changes in type II alveolar epithelial (ATII) cells, and SP-A and TTF-1 expression were analyzed. In vitro, rat ATII cells were obtained. SP-A and TTF-1 expression in cells was measured. ShRNA-TTF-1 transfection was performed to knock down TTF-1 expression. Our data showed that LPS-induced lung injury and increase in insulin level, and LPS-induced reduction of SP-A and TTF-1 expression in both the lung and cells, were significantly compromised by liraglutide. Furthermore, we also found that these effects of liraglutide were markedly blunted by shRNA-TTF-1. Taken together, our findings suggest that liraglutide enhances SP-A expression in ATII cells and attenuates pulmonary inflammation in LPS-induced ALI, most likely through the TTF-1 signaling pathway.

scholarly journals Evidences of Herbal Medicine-Derived Natural Products Effects in Inflammatory Lung Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Fernanda Paula R. Santana ◽  
Nathalia M. Pinheiro ◽  
Márcia Isabel B. Mernak ◽  
Renato F. Righetti ◽  
Mílton A. Martins ◽  
...  
Keyword(s):  
Natural Products ◽  
Herbal Medicine ◽  
Biological Activities ◽  
Biological Effects ◽  
Pulmonary Inflammation ◽  
Experimental Models ◽  
Chronic Obstructive ◽  
Anti Inflammatory

Pulmonary inflammation is a hallmark of many respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory syndrome distress (ARDS). Most of these diseases are treated with anti-inflammatory therapy in order to prevent or to reduce the pulmonary inflammation. Herbal medicine-derived natural products have been used in folk medicine and scientific studies to evaluate the value of these compounds have grown in recent years. Many substances derived from plants have the biological effectsin vitroandin vivo, such as flavonoids, alkaloids, and terpenoids. Among the biological activities of natural products derived from plants can be pointed out the anti-inflammatory, antiviral, antiplatelet, antitumor anti-allergic activities, and antioxidant. Although many reports have evaluated the effects of these compounds in experimental models, studies evaluating clinical trials are scarce in the literature. This review aims to emphasize the effects of these different natural products in pulmonary diseases in experimental models and in humans and pointing out some possible mechanisms of action.

scholarly journals In Vitro and In Vivo Performance of Dry Powder Inhalation Formulations: Comparison of Particles Prepared by Thin Film Freezing and Micronization

2014 ◽  
Vol 15 (4) ◽  
pp. 981-993 ◽  
Author(s):  
Yi-Bo Wang ◽  
Alan B. Watts ◽  
Jay I. Peters ◽  
Sha Liu ◽  
Ayesha Batra ◽  
...  
Keyword(s):  
Thin Film ◽  
Dry Powder Inhalation ◽  
Dry Powder ◽  
Thin Film Freezing

scholarly journals Pneumocystis Pneumonia Increases the Susceptibility of Mice to Sublethal Hyperoxia

2003 ◽  
Vol 71 (10) ◽  
pp. 5970-5978 ◽  
Author(s):  
James M. Beck ◽  
Angela M. Preston ◽  
Steven E. Wilcoxen ◽  
Susan B. Morris ◽  
Eric S. White ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cell ◽  
Cell Injury ◽  
Alveolar Epithelial Cell ◽  
Pulmonary Inflammation ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Epithelial Cell Injury

ABSTRACT Patients with Pneumocystis pneumonia often develop respiratory failure after entry into medical care, and one mechanism for this deterioration may be increased alveolar epithelial cell injury. In vitro, we previously demonstrated that Pneumocystis is not cytotoxic for alveolar epithelial cells. In vivo, however, infection with Pneumocystis could increase susceptibility to injury by stressors that, alone, would be sublethal. We examined transient exposure to hyperoxia as a prototypical stress that does cause mortality in normal mice. Mice were depleted of CD4+ T cells and inoculated intratracheally with Pneumocystis. Control mice were depleted of CD4+ T cells but did not receive Pneumocystis. After 4 weeks, mice were maintained in normoxia, were exposed to hyperoxia for 4 days, or were exposed to hyperoxia for 4 days followed by return to normoxia. CD4-depleted mice with Pneumocystis pneumonia demonstrated significant mortality after transient exposure to hyperoxia, while all uninfected control mice survived this stress. We determined that organism burdens were not different. However, infected mice exposed to hyperoxia and then returned to normoxia demonstrated significant increases in inflammatory cell accumulation and lung cell apoptosis. We conclude that Pneumocystis pneumonia leads to increased mortality following a normally sublethal hyperoxic insult, accompanied by alveolar epithelial cell injury and increased pulmonary inflammation.

scholarly journals In Vitro and In Vivo Assessment of PEGylated PEI for Anti-IL-8/CxCL-1 siRNA Delivery to the Lungs

Nanomaterials ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1248
Author(s):  
Alan J. Hibbitts ◽  
Joanne M. Ramsey ◽  
James Barlow ◽  
Ronan MacLoughlin ◽  
Sally-Ann Cryan
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Inflammation ◽  
Sirna Delivery ◽  
Airway Epithelial Cells ◽  
Lung Model ◽  
Airway Epithelial ◽  
In Vivo Models ◽  
Gene And Protein Expression

Inhalation offers a means of rapid, local delivery of siRNA to treat a range of autoimmune or inflammatory respiratory conditions. This work investigated the potential of a linear 10 kDa Poly(ethylene glycol) (PEG)-modified 25 kDa branched polyethyleneimine (PEI) (PEI-LPEG) to effectively deliver siRNA to airway epithelial cells. Following optimization with anti- glyceraldehyde 3-phosphate dehydrogenase (GAPDH) siRNA, PEI and PEI-LPEG anti-IL8 siRNA nanoparticles were assessed for efficacy using polarised Calu-3 human airway epithelial cells and a twin stage impinger (TSI) in vitro lung model. Studies were then advanced to an in vivo lipopolysaccharide (LPS)-stimulated rodent model of inflammation. In parallel, the suitability of the siRNA-loaded nanoparticles for nebulization using a vibrating mesh nebuliser was assessed. The siRNA nanoparticles were nebulised using an Aerogen® Pro vibrating mesh nebuliser and characterised for aerosol output, droplet size and fine particle fraction. Only PEI anti-IL8 siRNA nanoparticles were capable of significant levels of IL-8 knockdown in vitro in non-nebulised samples. However, on nebulization through a TSI, only PEI-PEG siRNA nanoparticles demonstrated significant decreases in gene and protein expression in polarised Calu-3 cells. In vivo, both anti-CXCL-1 (rat IL-8 homologue) nanoparticles demonstrated a decreased CXCL-1 gene expression in lung tissue, but this was non-significant. However, PEI anti-CXCL-1 siRNA-treated rats were found to have significantly less infiltrating macrophages in their bronchoalveolar lavage (BAL) fluid. Overall, the in vivo gene and protein inhibition findings indicated a result more reminiscent of the in vitro bolus delivery rather than the in vitro nebulization data. This work demonstrates the potential of nebulised PEI-PEG siRNA nanoparticles in modulating pulmonary inflammation and highlights the need to move towards more relevant in vitro and in vivo models for respiratory drug development.

scholarly journals High Molecular Weight Hyaluronan Suppresses Macrophage M1 Polarization and Enhances IL-10 Production in PM2.5-Induced Lung Inflammation

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1766 ◽  
Author(s):  
Qiwen Shi ◽  
Lan Zhao ◽  
Chenming Xu ◽  
Leifang Zhang ◽  
Hang Zhao
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Lung Inflammation ◽  
Macrophage Polarization ◽  
Pulmonary Inflammation ◽  
In Vivo Studies ◽  
Protective Effects ◽  
M1 Polarization

PM2.5 is particulate matter with a diameter of 2.5 μm or less. Airway macrophages are the key players regulating PM2.5-induced inflammation. High molecular weight hyaluronan (HMW-HA) has previously been shown to exert protective effects on PM2.5-induced acute lung injury and inflammation. However, little is known about the detailed mechanism. In this study, we aimed to determine whether HMW-HA alleviates PM2.5-induced pulmonary inflammation by modulating macrophage polarization. The levels of M1 biomarkers TNF-α, IL-1β, IL-6, CXCL1, CXCL2, NOS2 and CD86, as well as M2 biomarkers IL-10, MRC1, and Arg-1 produced by macrophages were measured by ELISA, qPCR, and flow cytometry. In addition, the amount of M1 macrophages in lung tissues was examined by immunofluorescence of CD68 and NOS2. We observed a decline in PM2.5-induced M1 polarization both in macrophages and lung tissues when HMW-HA was administered simultaneously. Meanwhile, western blot analysis revealed that PM2.5-induced JNK and p38 phosphorylation was suppressed by HMW-HA. Furthermore, in vitro and in vivo studies showed that co-stimulation with HMW-HA and PM2.5 promoted the expression and release of IL-10, but exhibited limited effects on the transcription of MRC1 and ARG1. In conclusion, our results demonstrated that HMW-HA ameliorates PM2.5-induced lung inflammation by repressing M1 polarization through JNK and p38 pathways and promoting the production of pro-resolving cytokine IL-10.

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