Therapy For Lung Disease Research Articles

The Efficacy and Safety of Pirfenidone Combined With Immunosuppressant Therapy in Connective Tissue Disease-Associated Interstitial Lung Disease: A 24-Week Prospective Controlled Cohort Study.

ObjectiveInterstitial lung disease (ILD) is a common manifestation of connective tissue disease (CTD) that manifests as several subtypes with significant differences in prognosis. It is necessary to evaluate the efficacy and safety of pirfenidone (PFD) combined with immunosuppressant (IS) in the treatment of CTD-ILD.MethodsA total of 111 patients with CTD-ILD were enrolled, including those with systemic sclerosis (SSc), inflammatory myopathy (IIM), rheumatoid arthritis (RA), and other CTDs (such as systemic lupus erythematosus, primary Sjogren's syndrome, and undifferentiated CTD). After evaluation of the high-resolution computed tomography (HRCT), pulmonary function (PF), and basic disease activity, patients either were or were not prescribed PFD and were followed up regularly for 24 weeks.ResultsAfter 24 weeks of treatment, predicted forced vital capacity (FVC%) in the SSc-PFD group had improved by 6.60%, whereas this value was 0.55% in patients with SSc-no-PFD. The elevation in FVC% was also significant in IIM-PFD over the IIM-no-PFD controls (7.50 vs. 1.00%). The predicted diffusing capacity for carbon monoxide (DLCo%) of RA-PFD was enhanced by 7.40%, whereas that of RA-no-PFD decreased by 5.50%. When performing a subtype analysis of HRCT images, the change in FVC% among patients with SSc with a tendency toward usual interstitial pneumonia (UIP) was higher in those given PFD (SSc-PFD-UIP) than the no-PFD group (8.05 vs. −3.20%). However, in IIM patients with a non-UIP tendency, PFD displayed better therapeutic effects than the control (10.50 vs. 1.00%). DLCo% improved significantly in patients with the PFD-treated RA-non-UIP subtype compared with the patients with no-PFD (10.40 vs. −4.45%). Dichotomizing the patients around a baseline FVC% or DLCo% value of 70%, the PFD arm had a more improved FVC% than the no-PFD arm within the high-baseline-FVC% subgroups of patients with SSc and IIM (6.60 vs. 0.10%, 6.30 vs. 1.10%). In patients with RA-PFD, DLCo% showed a significant increase in the subgroup with low baseline DLCo% compared to that in patients with RA-no-PFD (7.40 vs. −6.60%).ConclusionThe response of PF to PFD varied between CTD-ILD subsets. Patients with SSc and IIM showed obvious improvements in FVC%, especially patients with SSc-UIP and IIM-non-UIP. In RA, the subsets of patients with non-UIP and a lower baseline DLCo% most benefited from PFD.

Mass spectrometry detection of inhaled drug in distal fibrotic lung

BackgroundCurrently the only available therapies for fibrotic Interstitial Lung Disease are administered systemically, often causing significant side effects. Inhaled therapy could avoid these but to date there is no evidence that drug can be effectively delivered to distal, fibrosed lung. We set out to combine mass spectrometry and histopathology with rapid sample acquisition using transbronchial cryobiopsy to determine whether an inhaled drug can be delivered to fibrotic, distal lung parenchyma in participants with Interstitial Lung Disease.MethodsPatients with radiologically and multidisciplinary team confirmed fibrotic Interstitial Lung Disease were eligible for this study. Transbronchial cryobiopsies and endobronchial biopsies were taken from five participants, with Interstitial Lung Disease, within 70 min of administration of a single dose of nebulised ipratropium bromide. Thin tissue cryosections were analysed by Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging and correlated with histopathology. The remainder of the cryobiopsies were homogenised and analysed by Liquid Chromatography—tandem Mass Spectrometry.ResultsDrug was detected in proximal and distal lung samples from all participants. Fibrotic regions were identified in research samples of four of the five participants. Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging showed co-location of ipratropium with fibrotic regions in samples from three participants.ConclusionsIn this proof of concept study, using mass spectrometry, we demonstrate for the first-time that an inhaled drug can deposit in distal fibrotic lung parenchyma in patients with Interstitial Lung Disease. This suggests that drugs to treat pulmonary fibrosis could potentially be administered by the inhaled route.Trial registration A prospective clinical study approved by London Camden and Kings Cross Research Ethics Committee and registered on clinicaltrials.gov (NCT03136120)

Genetic diagnosis of immune dysregulation can lead to targeted therapy for interstitial lung disease: A case series and single center approach.

In recent years, a growing number of monogenic disorders have been described that are characterized by immune dysregulation. A subset of these "primary immune regulatory disorders" can cause severe interstitial lung disease, often recognized in late childhood or adolescence. Patients presenting to pulmonary clinic may have long and complex medical histories, but lack a unifying genetic diagnosis. It is crucial for pulmonologists to recognize features suggestive of multisystem immune dysregulation and to initiate genetic workup, since targeted therapies based on underlying genetics may halt or even reverse pulmonary disease progression. Through such an approach, our center has been able to diagnose and treat a cohort of patients with interstitial lung disease from gene defects that affect immune regulation. Here we present representative cases related to pathogenic variants in three distinct pathways and summarize disease manifestations and treatment approaches. We conclude with a discussion of our perspective on the outstanding challenges for diagnosing and managing these complex life-threatening and chronic disorders.

Costs of oxygen therapy for interstitial lung disease and chronic obstructive pulmonary disease: A retrospective study from a universal healthcare system

RATIONALE & OBJECTIVES: Oxygen is prescribed for patients with interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). This study compared the per capita financial costs of home oxygen therapy in ILD and COPD. METHODS Adults with either ILD or COPD who initiated home oxygen between 2010-2017 at the Vancouver Coastal Health Home Oxygen Program were analyzed retrospectively using a chart review. The monthly cost of oxygen equipment, home visits by oxygen providers and respiratory therapists, as well as overnight oximetry studies, were collected for each year of oxygen utilization, adjusted to 2018 Canadian Dollars. The Wilcoxon Rank Sum Test was used to compare monthly oxygen costs and flow rates between the two diseases. MEASUREMENTS AND RESULTS: A total of 99 patients with ILD and 1017 with COPD initiated oxygen therapy between 2010-2017. Both cohorts had a higher per capita cost of home oxygen in month 1 compared to months 2-24 (ILD: ($202.57 ± $88.88 versus $142.21 ± $59.01, P < 0.001; COPD: $222.85 ± $102.52 versus $156.65 ± $60.50, P < 0.001). COPD was more costly after the initial month, corresponding to greater frequency of using continuous long-term oxygen compared to oxygen only with ambulation. Patients with ILD had higher mean ambulatory oxygen flow rate for all months (P < 0.001). CONCLUSION Per capita costs of home oxygen therapy were comparable between ILD and COPD, with the main difference in costs related to the use of ambulatory versus continuous long-term oxygen. These findings will aid healthcare budget planning for both ILD and COPD.

Everolimus-Induced Pneumonitis in Patients with Neuroendocrine Neoplasms: Real-World Study on Risk Factors and Outcomes

BackgroundEverolimus-induced pneumonitis (EiP) has been poorly studied in patients with neuroendocrine neoplasms (NEN) outside clinical trials. The aim of this study was to evaluate the incidence, risk factors, and outcomes of EiP in patients with NENs using real-world data.MethodsRetrospective study of everolimus-treated patients with advanced NENs. Imaging reports were systematically reviewed for the presence of pneumonitis. Clinical features and treatment profiles for EiP were summarized. Overall survival (OS) was calculated from the initiation of everolimus to the date of death or last follow-up using the Kaplan-Meier method.ResultsA total of 122 patients were included. Median age at start of everolimus was 62 (19-86) years, 62% (76/122) were male, and half were from pancreatic origin (62, 51%). Twenty-eight patients (23%) developed EiP: 82% grade (G)1 or G2, 14% G3 and 4% G4. The median time to EiP was 3.6 (0.8-51) months. Primary tumor site, concurrent lung disease, smoking history, and prior therapies were not associated with the onset of EiP. Patients who developed EiP had longer time on everolimus treatment (median 18 months vs 6 months; P = .0018) and OS (77 months vs 52 months; P = .093). Everolimus-induced pneumonitis was a predictor of improved OS by multivariable analysis (HR 0.39, 95% CI 0.19-0.82; P = .013).ConclusionEverolimus-induced pneumonitis in the real-world clinical setting is present in one quarter of patients with NENs receiving everolimus and often occurs early. While risk factors for EiP were not identified, patients with EiP had improved survival.

An in vivo model for extracellular vesicle-induced emphysema.

Chronic obstructive pulmonary disease (COPD) is a debilitating chronic disease and the third-leading cause of mortality worldwide. It is characterized by airway neutrophilia, promoting tissue injury through release of toxic mediators and proteases. Recently, it has been shown that neutrophil-derived extracellular vesicles (EVs) from lungs of patients with COPD can cause a neutrophil elastase–dependent (NE-dependent) COPD-like disease upon transfer to mouse airways. However, in vivo preclinical models elucidating the impact of EVs on disease are lacking, delaying opportunities for therapeutic testing. Here, we developed an in vivo preclinical mouse model of lung EV–induced COPD. EVs from in vivo LPS-activated mouse neutrophils induced COPD-like disease in naive recipients through an α-1 antitrypsin–resistant, NE-dependent mechanism. Together, these results show a key pathogenic and mechanistic role for neutrophil-derived EVs in a mouse model of COPD. Broadly, the in vivo model described herein could be leveraged to develop targeted therapies for severe lung disease.

Impact of Concomitant Medication Burden on Tolerability of Disease-targeted Therapy and Survival in Interstitial Lung Disease.

Rationale: Multimorbidity is common and leads to substantial concomitant medication burden in patients with interstitial lung disease (ILD), which may affect tolerability of ILD-targeted medications and health outcomes. Objectives: To determine the associations of concomitant medication burden with tolerability of ILD-targeted medications and survival in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF ILD. Methods: Patients with IPF receiving nintedanib or pirfenidone and patients with non-IPF ILD receiving azathioprine or mycophenolate were identified from two Australian and Canadian registries. Baseline concomitant medication burden was evaluated using three measures: medication count, polypharmacy (⩾5 medications), and the medication regimen complexity index (MRCI). Medication intolerance and discontinuation were evaluated at 6 months and 1 year after initiation of ILD-targeted medications, respectively. Cox regression models and likelihood ratio tests were used to determine the prognostic significance of medication burden on transplant-free survival. Results: In 645 treated patients with IPF, 43% experienced adverse reactions leading to intolerance (defined as dose reduction, temporary dose interruption, or permanent drug discontinuation) of antifibrotic medications within 6 months of initiation, with high baseline concomitant medication burden being consistently associated with intolerance (medication count: P = 0.005; polypharmacy: P = 0.006; MRCI: P = 0.004). This association was not observed for immunosuppressive medications in 1,255 treated patients with non-IPF ILD, who also had a lower intolerance (18%). Baseline concomitant medication burden was not independently associated with permanent discontinuation of antifibrotic (29%) and immunosuppressive medications (20%) at 1 year. The MRCI was the only measure of concomitant medication burden associated with transplant-free survival in both cohorts (P < 0.01 for both), which improved prognostication beyond common clinical factors and the ILD-GAP index (P < 0.001 for both). Conclusions: Concomitant medication burden is associated with intolerance of antifibrotic medications in patients with IPF. Medication regimen complexity is superior to simpler evaluation of concomitant medication burden for predicting prognosis in ILD.

Autocrine, Paracrine, and Endocrine Signals That Can Alter Alveolar Macrophages Function.

Alveolar macrophages (AMs) are extremely versatile cells with complex functions involved in health or diseases such as pneumonia, asthma, and pulmonary alveolar proteinosis. In recent years, it has been widely identified that the different functions and states of macrophages are the results from the complex interplay between microenvironmental signals and macrophage lineage. Diverse and complicated signals to which AMs respond are mentioned when they are described individually or in a particular state of AMs. In this review, the microenvironmental signals are divided into autocrine, paracrine, and endocrine signals based on their secreting characteristics. This new perspective on classification provides a more comprehensive and systematic introduction to the complex signals around AMs and is helpful for understanding the roles of AMs affected by physiological environment. The existing possible treatments of AMs are also mentioned in it. The thorough understanding of AMs signals modulation may be contributed to the development of more effective therapies for AMs-related lung diseases.

Telomere Shortening and Its Association with Cell Dysfunction in Lung Diseases.

Telomeres are localized at the end of chromosomes to provide genome stability; however, the telomere length tends to be shortened with each cell division inducing a progressive telomere shortening (TS). In addition to age, other factors, such as exposure to pollutants, diet, stress, and disruptions in the shelterin protein complex or genes associated with telomerase induce TS. This phenomenon favors cellular senescence and genotoxic stress, which increases the risk of the development and progression of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, SARS-CoV-2 infection, and lung cancer. In an infectious environment, immune cells that exhibit TS are associated with severe lymphopenia and death, whereas in a noninfectious context, naïve T cells that exhibit TS are related to cancer progression and enhanced inflammatory processes. In this review, we discuss how TS modifies the function of the immune system cells, making them inefficient in maintaining homeostasis in the lung. Finally, we discuss the advances in drug and gene therapy for lung diseases where TS could be used as a target for future treatments.

Inhibition of the Arp2/3 complex represses human lung myofibroblast differentiation and attenuates bleomycin-induced pulmonary fibrosis.

The Arp2/3 multiprotein complex regulates branched polymerisation of the actin cytoskeleton and may contribute to collagen synthesis and fibrogenesis in the lung. Expression of Arp2/3 components was assessed in human lung fibroblasts and in the bleomycin-induced pulmonary fibrosis model in mice. The Arp2/3 complex was repressed with the allosteric inhibitor CK666 and with interfering RNAs targeting the ARP2, ARP3 and ARPC2 subunits (siARP2, siARP3 and siARPC2) in CCD-16Lu human lung fibroblasts in vitro. Mice received daily intraperitoneal injections of CK666 from the 7th to the 14th day after tracheal bleomycin instillation. Expression of Arp2/3 complex subunits mRNAs was increased in fibroblasts treated with TGF-β1 and in the lungs of bleomycin-treated mice compared with controls. In vitro, CK666 and siARPC2 inhibited cell growth and TGF-β1-induced α-smooth muscle actin (ACTA2) and collagen-1 (COL1) expression. CK666 also decreased ACTA2 and COL1 expression in unstimulated cells. CK666 reduced Akt phosphorylation and repressed phospho-GSK3β, β-catenin and MRTF-A levels in unstimulated fibroblasts. In vivo, CK666 reduced levels of both procollagen-1 and insoluble collagen in bleomycin-treated mice. Expression of the Arp2/3 complex was increased in profibrotic environments in vitro and in vivo. Inhibition of the Arp2/3 complex repressed ACTA2 and COL1 expression and repressed an Akt/phospho-GSK3β/β-catenin/MRTF-A pathway in lung fibroblasts. CK666 exerted antifibrotic properties in the lung in vivo. Inhibition of the Arp2/3 complex could represent an interesting new therapy for idiopathic pulmonary fibrosis and other fibrotic interstitial lung diseases.

O24‐4: Impact of medication burden on tolerability of disease‐targeted therapy and survival in interstitial lung disease

O24‐4: Impact of medication burden on tolerability of disease‐targeted therapy and survival in interstitial lung disease

Inhaled gene therapy of preclinical muco-obstructive lung diseases by nanoparticles capable of breaching the airway mucus barrier

IntroductionInhaled gene therapy of muco-obstructive lung diseases requires a strategy to achieve therapeutically relevant gene transfer to airway epithelium covered by particularly dehydrated and condensed mucus gel layer. Here, we...

Dexamethasone in acute cardiopulmonary syndrome with hyperinflammatory state

Abstract Introduction Elderly patient hospitalized due to acute heart failure often have a concomitant acute lung disease (acute bronchitis, pneumonia, chronic obstructive pulmonary disease-COPD- exacerbation). Establishing the role of each disease in a clinical picture of acute cardiopulmonary syndrome can be challenging. Procalcitonin has been used as a guide to antibiotic therapy with contrasting results. A common thread of these diseases is inflammation; a hyperinflammatory response determines more serious symptoms and a worse prognosis. Purpose We evaluated the effectiveness of a treatment with dexamethasone in patients with acute cardiopulmonary syndrome and a strong inflammatory response. Materials and methods We evaluated 157 consecutive HFPEF (heart failure with preserved ejection fraction) patients ≥80 years of age, with concomitant symptoms attributable to acute bronchitis, pneumonia, or COPD exacerbation, hospitalized due to worsening dyspnoea, with an NT-proBNP ≥3,000 pg/ml, and a finding X-ray of lung congestion with or without a consolidation. Reactive C Protein was measured. Patients with SARS-CoV-2, indication to corticosteroids use for other clinical conditions or need for mechanical ventilation were excluded. The 96 patients with values&amp;gt;20 mg/dl were randomized into 2 groups: 48 patients were treated open-label with dexamethasone at a dose of 8 mg iv/day for a maximun of ten days, in addition to the usual therapies for acute heart failure and lung disease, while the same number of patients were treated with the usual therapy. In both groups the antibiotic was administered only if the procalcitonin was≥0.25 μg/L. Clinical recovery time, length of hospitalization, in-hospital mortality, the need for a new hospitalization and mortality at one month were evaluated. Results The mean age of the patients was 88±4 years in the dexamethasone group and 87±5 in the usual therapy group. The results are shown in Table 1. Patients treated with dexamethasone experienced a faster clinical recovery and a shorter length of hospitalization. No significant differences were found regarding either in-hospital mortality or need for rehospitalization and mortality at 30 days. Conclusions Very elderly patients with acute cardiopulmonary syndrome and hyperinflammatory state associated with an excessive increase in Reactive Protein C have a favorable response to dexamethasone therapy in addition to the usual therapy in terms of clinical improvement and length of hospitalization. Our case history is small to evaluate a possible improvement in mortality. These findings need to be consolidated from double-blind randomized controlled trials Funding Acknowledgement Type of funding sources: None. Table 1

Disparities in heart and lung transplantation.

Cardiothoracic transplantation is the definitive therapy for end-stage heart and lung disease. In service to this population, disparities in access and care must be simultaneously understood and addressed. There are sex, race, geographic, age, and underlying disease disparities in both heart and lung transplantation. Women have reduced waitlist survival but improved posttransplant survival when compared with men for both heart and lung transplantation. Black patients have worse outcome compared with other races postheart transplant. Geographic disparities impact the likelihood of receiving heart or lung transplant and the growing number of patients with advanced age seeking transplant complicates discussions on survival benefit. Finally, underlying disease has affected outcomes for both heart and lung transplant and now are incorporated into the allocation system. Though heart and lung transplantation have several existing disparities, it remains to be seen how advancements in medical technology, changes in donor organ allocation policies, and growing experience in patient selection will impact these concerns.

Mesenchymal stromal cell extracellular vesicles as therapy for acute and chronic respiratory diseases: A meta-analysis.

Preclinical studies suggest mesenchymal stromal cell extracellular vesicles (MSC‐EVs) reduce inflammation and improve organ function in lung diseases; however, an objective analysis of all available data is needed prior to translation. Using rigorous meta‐research methods, we determined the effectiveness of MSC‐EVs for preclinical respiratory diseases and identified experimental conditions that may further refine this therapy. A systematic search of MEDLINE/Embase identified 1167 records. After screening, 52 articles were included for data extraction and evaluated for risk of bias and quality of reporting in study design. A random effects meta‐analysis was conducted for acute lung injury (ALI; N = 23), bronchopulmonary dysplasia (BPD; N = 8) and pulmonary arterial hypertension (PAH; N = 7). Subgroup analyses identified EV methods/characteristics that may be associated with improved efficacy. Data is presented as standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI). For ALI, MSC‐EVs markedly reduced lung injury (SMD ‐4.33, CI ‐5.73 to ‐2.92), vascular permeability (SMD ‐2.43, CI ‐3.05 to ‐1.82), and mortality (RR 0.39, CI 0.22 to 0.68). Small EVs were more consistently effective than large EVs whereas no differences were observed between tissue sources, immunocompatibility or isolation techniques. For BPD, alveolarization was improved by MSC‐EVs (SMD ‐1.45, CI ‐2.08 to ‐0.82) with small EVs more consistently beneficial then small/large EVs. In PAH, right ventricular systolic pressure (SMD ‐4.16, CI ‐5.68 to ‐2.64) and hypertrophy (SMD ‐2.80, CI ‐3.68 to ‐1.91) were significantly attenuated by EVs. In BPD and PAH, EVs isolated by ultracentrifugation demonstrated therapeutic benefit whereas tangential flow filtration (N = 2) displayed minimal efficacy. Lastly, risk of bias and quality of reporting for experimental design were consistently unclear across all studies. Our findings demonstrate clear potential of MSC‐EVs to be developed as therapy for acute and chronic lung diseases. However, greater transparency in research design and direct comparisons of isolation technique and EV subtypes are needed to generate robust evidence to guide clinical translation.Protocol Registration: PROSPERO CRD42020145334

PH Roundtable: Conundrums and Controversies in PH-ILD: To Treat or Not to Treat—Identifying Optimal Treatment Candidates

PH Roundtable: Conundrums and Controversies in PH-ILD: To Treat or Not to Treat—Identifying Optimal Treatment Candidates

Mesenchymal Stem Cells and Clinical Application in Chronic Lung Diseases

Mesenchymal stem cells are a multipotent mature non hematopoietic stem cells, with characteristics such as ability to self-renew and differentiate in mesodermal, ectodermal, and endodermal pathway. Mesenchymal stem cells also secrete cytokine and immunoreceptor which regulate micro environment in host tissues and angiogenic mediators which are able to improve damaged tissues. Mesenchymal stem cells are obtained from the human body by isolation, culture, proliferation, characterization, and/or differentiation originating from fat cells (adipose), periosteum tissue, and other tissues from the body. Mesenchymal stem cells can be obtained by autologous and allogenic way. Stem cell processing includes isolation, proliferation, differentiation, and temporary storage for clinical application adhering to good drug manufacturing practice. Approach to cell therapy and bioengineering in lung disease is rapidly developing in the last 10 years. In the current era of cell therapy and transplantation, a lot of research has been done to understand and develop mesenchymal stem cells as a therapeutic alternative, particularly in respiratory area.

Could melatonin be an adjunct therapy for post-TB lung disease?

Post-tuberculosis (post-TB) lung disease is a complex interplay between organism, host, and environmental factors, and it affects long-term respiratory health. It associates with underlying processes such as inflammation, fibrosis, and oxidative stress. Decades of research has demonstrated melatonin as a potent anti-inflammatory, anti-fibrotic, antioxidant, and vasodilatory agent. These effects have been observed in numerous experimental and clinical models of lung diseases. Moreover, melatonin has significant anti-microbial activity, which has also been observed in the context of TB bacterial growth. It is worth pointing out that these effects of melatonin are a reminder of the pathologic processes that underpin post-TB lung disease. Based on the intriguing evidence presented and discussed in this paper, melatonin could be considered a safe, affordable, and adjunct therapy against post-TB lung disease. Melatonin may provide health benefits in this context, mediated via its anti-inflammatory, anti-fibrotic, vasodilatory, antimicrobial and antioxidant properties.

Dual-Functional Dendrimer Micelles with Glycyrrhizic Acid for Anti-Inflammatory Therapy of Acute Lung Injury.

Dendrimer micelles with glycyrrhizic acid (GA) were developed for anti-inflammatory therapy of acute lung injury (ALI). Cholesterol was conjugated to histidine- and arginine-grafted polyamidoamine (PamHR) for micelle formation. The cholesterol-conjugated PamHR (PamHRchol) was mixed with amphiphilic GA to produce PamHRchol/GA mixed micelles. The GA integrated into the micelles had two functions: it acted as an anti-inflammatory drug and facilitated intracellular gene delivery. The PamHRchol/GA micelles formed stable complexes with plasmid DNA. Integrating GA into the micelles increased their transfection efficiency. Confocal microscopy and flow-cytometry studies confirmed that the PamHRchol/GA micelles improved cellular uptake compared with PamHRchol. A competition assay with free GA suggested that the enhanced transfection efficiency of the micelles might be due to the interaction between GA and its receptor. In addition, GA has a membrane-destabilizing effect, and a chloroquine pretreatment assay confirmed that GA increased endosomal escape. Furthermore, the PamHRchol/GA micelles reduced tumor necrosis factor-α in lipopolysaccharide-activated Raw264.7 cells, suggesting a mechanism for its anti-inflammatory effects. To evaluate the therapeutic potential of the PamHRchol/GA micelles, the heme oxygenase-1 (HO-1) gene was delivered into the lungs of mice with ALI. The PamHRchol/GA micelles had higher gene delivery efficiency into the lungs than polyethylenimine (25 kDa, PEI25k) and the PamHRchol micelles. The combined effects of the HO-1 gene and GA produced effective anti-inflammation response in the lungs of the ALI animals. Therefore, the dual-function PamHRchol/GA micelles, which acted as an anti-inflammatory drug and a gene carrier, could be a useful therapy for inflammatory lung diseases.

Cocculus hirsutus ameliorates gastric and lung injuries by suppressing Src/Syk

BackgroundCocculus hirsutus (L.) W. Thedo., a traditionally well-known plant, has confirmed antitumor properties as well as acute and chronic diuretic effects. However, little is known about its inflammatory activities and the potential effect on inflammatory disease treatment. PurposeOur aim in this study was to explore additional beneficial properties of C. hirsutus ethanol extract (Ch-EE) such as anti-inflammatory activity in vitro and in vivo as well as its underlying mechanisms and to provide a theoretical basis for its role as a candidate natural drug in clinical gastritis and lung disease therapy. Study DesignRAW264.7 cells, HEK293T cells, peritoneal macrophages, and mouse models of acute gastritis and acute lung injury were used to assess the anti-inflammatory activity of Ch-EE. MethodsDecreases in LPS-induced nitric oxide (NO) production and cytokine expression by RAW264.7 cells after Ch-EE treatment were evaluated by Griess assays and PCR, respectively. Transcription factor activity was assessed through luciferase reporter gene assay, and protein expression was determined by Western blotting analysis. Overexpression assays and cellular thermal shift assays were executed in HEK293T cells. Our two in vivo models were an HCl/EtOH-induced gastritis model and an LPS-induced lung injury model. Changes in stomach lesions, lung edema, and lung histology were examined upon treatment with Ch-EE. Components of Ch-EE were determined by liquid chromatography-mass spectrometry. ResultsLPS-induced nitric oxide production and Pam3CSK4- and L-NAME-induced NO production were inhibited by Ch-EE treatment of RAW264.7 cells. Furthermore, LPS-induced increases in transcript levels of iNOS, COX2, CCL12, and IL-1β were reduced by Ch-EE treatment. Ch-EE decreased both MyD88- and TRIF-induced NF-κB promotor activity. Proteins upstream of NF-κB, namely p-p50, p-p65, p-IκBα, p-AKT1, p-Src, and p-Syk, were all downregulated by Ch-EE. Moreover, Src and Syk were targets of Ch-EE. Ch-EE treatment reduced the size of inflammatory stomach lesions induced by HCl/EtOH, lung edema, and accumulation of activated neutrophils caused by LPS. ConclusionsThese results strongly suggest that Cocculus hirsutus can be developed as a promising anti-inflammatory remedy with Src- and Syk-inhibitory functions targeting diseases related to gastritis and lung injury.