- P311 Promotes Lung Fibrosis via Stimulation of TGF-β1, 2 and 3 Translation. [Journal Article]
- AJAm J Respir Cell Mol Biol 2018 Sep 19
- Interstitial lung fibrosis, a frequently idiopathic and fatal disease, has been linked to the increased expression of profibrotic TGF-βs. P311 is an RNA-binding protein, which stimulates TGF-β1, 2 an...
Interstitial lung fibrosis, a frequently idiopathic and fatal disease, has been linked to the increased expression of profibrotic TGF-βs. P311 is an RNA-binding protein, which stimulates TGF-β1, 2 and 3 translation in several cell types through its interaction with the eukaryotic translation initiation factor 3b. Here we report that P311 is switched on in the lungs of Idiopathic pulmonary fibrosis (IPF) patients and in the mouse model of bleomycin (BLM)-induced pulmonary fibrosis. To assess the in vivo role of P311 in lung fibrosis, BLM was instilled into the lungs of P311 knockout (KO) mice where fibrotic changes were significantly decreased in tandem with a reduction in TGF-β1, 2 and 3 levels/activity compared to BLM-treated wild type (WT) mice. Complementing these findings, forced P311 expression increased TGF-βs level/activity in mouse and human lung fibroblasts, thereby leading to an activated phenotype with increased collagen production, as seen in IPF. Consistent with a specific effect of P311 on TGF-βs translation, TGF-β1, 2 and 3 neutralizing antibodies downregulated P311-induced collagen production by lung fibroblasts. Furthermore, treatment of BLM-exposed P311 KOs with recombinant TGF-β1, 2 and 3 induced pulmonary fibrosis to a degree similar to that found in BLM-treated WT mice. These studies demonstrate the essential function of P311 in TGF-βs-mediated lung fibrosis. Targeting P311 could prove efficacious in ameliorating the severity of IPF while circumventing the development of autoimmune complications and toxicities associated with the use of global TGF-β inhibitors.
- Coexisting cystic lung disease as a rare extra-renal manifestation of autosomal dominant polycystic kidney disease. [Journal Article]
- RCRadiol Case Rep 2018; 13(5):1048-1052
- Autosomal dominant polycystic kidney disease (ADPKD) classically presents with multiple bilateral renal cysts and ultimately progresses to end stage renal disease. While many of the extra-renal manif...
Autosomal dominant polycystic kidney disease (ADPKD) classically presents with multiple bilateral renal cysts and ultimately progresses to end stage renal disease. While many of the extra-renal manifestations of ADPKD are well-documented, associated pulmonary findings are particularly rare, having only been recently been reported in a handful of studies to date. A 69-year-old female with ADPKD presented to our hospital with respiratory complaints. High resolution computed tomography revealed bronchiectasis, cystic lung disease, and interstitial fibrosis. The patient did not have concurrent risk factors or coexisting disease processes to explain the etiology of her airway and cystic lung disease, which we suggest are manifestations of ADPKD. We have not found a previous report of interstitial lung disease in this setting.
- Allograft Inflammatory Factor 1 as an Immunohistochemical Marker for Macrophages in Multiple Tissues and Laboratory Animal Species. [Journal Article]
- CMComp Med 2018 Sep 18
- Allograft inflammatory factor 1 (AIF1) is a commonly used marker for microglia in the brains of humans and some animal models but has had limited applications elsewhere. We sought to determine whethe...
Allograft inflammatory factor 1 (AIF1) is a commonly used marker for microglia in the brains of humans and some animal models but has had limited applications elsewhere. We sought to determine whether AIF1 can be used as a macrophage marker across common laboratory animal species and tissues. We studied tissues (that is, spleen, liver, and lung) with defined macrophage populations by using an AIF1 immunostaining technique previously validated in human tissue. Tissues were collected from various mouse strains (n = 20), rat strains (n = 15), pigs (n = 4), ferrets (n = 4), and humans (n = 4, lung only). All samples of liver had scattered immunostaining in interstitial cells, consistent with resident tissue macrophages (Kupffer cells). Spleen samples had cellular immunostaining of macrophages in both the red and white pulp compartments, but the red pulp had more immunostained cellular aggregates and, in some species, increased immunostaining intensity compared with white pulp. In lung, alveolar macrophages had weak to moderate staining, whereas interstitial and perivascular macrophages demonstrated moderate to robust staining. Incidental lesions and tissue changes were detected in some sections, including a tumor, inducible bronchus-associated lymphoid tissue, and inflammatory lesions that demonstrated AIF1 immunostaining of macrophages. Finally, we compared AIF1 immunostaining of alveolar macrophages between a hypertensive rat model (SHR strain) and a normotensive model (WKY strain). SHR lungs had altered intensity and distribution of immunostaining in activated macrophages compared with macrophages of WKY lungs. Overall, AIF1 immunostaining demonstrated reproducible macrophage staining across multiple species and tissue types. Given the increasing breadth of model species used to study human disease, the use of cross-species markers and techniques can reduce some of the inherent variability within translational research.
- Inhalation treatment of idiopathic pulmonary fibrosis with curcumin large porous microparticles. [Journal Article]
- IJInt J Pharm 2018 Sep 15
- Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high mortality and poor prognosis. Curcumin shows anti-inflammatory effect by suppressing pro-inflammatory cytokine...
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high mortality and poor prognosis. Curcumin shows anti-inflammatory effect by suppressing pro-inflammatory cytokines and inhibiting NF-κB mediated inflammation. Here, we developed inhalable curcumin-loaded poly(lactic-co-glycolic)acid (PLGA) large porous microparticles (LPMPs) for the treatment of IPF. Curcumin LPMPs were rough and loose particles with many pores on the surfaces and channels in the inner spaces. The mean geometric diameter of them was larger than 10 µm while the aerodynamic diameter was only 3.12 µm due to their porous structures. They showed a fine particle fraction (FPF) less than 4.46 μm of 13.41%, 71% cumulative release after 9 h, and more importantly, they avoided uptake by alveolar macrophages. Therefore, most of released curcumin had opportunities to enter lung tissues. Rat pulmonary fibrosis models were established via once intratracheal administration of bleomycin. Curcumin powders and curcumin LPMPs were administered on Days 2, 7, 14, and 21. Curcumin LPMPs remarkably attenuated lung injuries, decreased hydroxyproline contents, reduced the synthesis of collagen I, and inhibited the expressions of TNF-α, TGF-β1, NF-κB p65 and MMP9. Moreover, curcumin LPMPs showed higher antifibrotic activity than curcumin powders. Curcumin LPMPs are a promising inhalable medication for the treatment of IPF.
- Survival rate, causes of death, and risk factors in systemic sclerosis: a large cohort study. [Journal Article]
- CRClin Rheumatol 2018 Sep 18
- To investigate the clinical pattern, survival rate, causes of death and risk factors in a large cohort of Chinese Han patients with systemic sclerosis (SSc). Inpatients treated from 2002 to 2014 were...
To investigate the clinical pattern, survival rate, causes of death and risk factors in a large cohort of Chinese Han patients with systemic sclerosis (SSc). Inpatients treated from 2002 to 2014 were included in this study. Patients were classified into diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc-overlap syndrome groups. Data were analyzed using Chi-squared tests, Kaplan-Meier curves, log-rank tests, and Cox proportional hazards modeling. Among a total of 201 patients, dcSSc (50.2%) was the major subtype, followed by lcSSc (30.3%) and SSc-overlap (19.4%). Interstitial lung disease (ILD, 148/201, 74%) was the most frequent organ involvement. The overall survival rates were 98% and 95% at 5 and 10 years, respectively. The overall standard mortality ratio (SMR) was 2.22. The most common cause of death was ILD combined with infection (8/16, 50%), followed by kidney failure (2/16, 12.5%). On crude analysis, pulmonary hypertension, ILD, cardiac involvements, renal involvements, and digital ischemia were associated with poor prognosis. On multivariate analysis, pericardial effusion (p = 0.000) and digital ischemia (p = 0.016) were independent prognostic factors of death. The mortality rate of patients with SSc is mildly increased in comparison with the general population. ILD is the most common systemic involvement and the principal cause of death in SSc. Pericardial effusion and digital ischemia are independent factors associated with death.
- Drug-Induced Interstitial Lung Disease from a Misdiagnosed Infection. [Journal Article]
- MIMicrobiol Insights 2018; 11:1178636118798371
- Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON. [Journal Article]
- LRLancet Respir Med 2018 Sep 14
- CONCLUSIONS: These findings suggest that nintedanib has a manageable safety and tolerability profile over long-term use, with no new safety signals. Patients with idiopathic pulmonary fibrosis could use nintedanib over the long-term to slow disease progression.
- Phosphatidylethanolamine Induces an Antifibrotic Phenotype in Normal Human Lung Fibroblasts and Ameliorates Bleomycin-Induced Lung Fibrosis in Mice. [Journal Article]
- IJInt J Mol Sci 2018 Sep 14; 19(9)
- Lung surfactant is a complex mixture of phospholipids and specific proteins but its role in the pathogenesis of interstitial lung diseases is not established. Herein, we analyzed the effects of three...
Lung surfactant is a complex mixture of phospholipids and specific proteins but its role in the pathogenesis of interstitial lung diseases is not established. Herein, we analyzed the effects of three representative phospholipid components, that is, dipalmitoilphosphatidylcoline (DPPC), phosphatidylglycerol (PG) and phosphatidylethanolamine (PE), on collagen expression, apoptosis and Ca2+ signaling in normal human lung fibroblasts (NHLF) and probed their effect in an experimental model of lung fibrosis. Collagen expression was measured with RT-PCR, apoptosis was measured by using either the APOPercentage assay kit (Biocolor Ltd., Northern Ireland, UK) or the Caspase-Glo 3/7 assay (Promega, Madison, WI, USA) and Ca2+ signaling by conventional epifluorescence imaging. The effect in vivo was tested in bleomycin-induced lung fibrosis in mice. DPPC and PG did not affect collagen expression, which was downregulated by PE. Furthermore, PE promoted apoptosis and induced a dose-dependent Ca2+ signal. PE-induced Ca2+ signal and apoptosis were both blocked by phospholipase C, endoplasmic reticulum pump and store-operated Ca2+ entry inhibition. PE-induced decrease in collagen expression was attenuated by blocking phospholipase C. Finally, surfactant enriched with PE and PE itself attenuated bleomycin-induced lung fibrosis and decreased the soluble collagen concentration in mice lungs. This study demonstrates that PE strongly contributes to the surfactant-induced inhibition of collagen expression in NHLF through a Ca2+ signal and that early administration of Beractant enriched with PE diminishes lung fibrosis in vivo.
- Pretreatment 18F-fluorodeoxyglucose Uptake in the Lung Parenchyma Predicts Poor Survival After Stereotactic Body Radiation Therapy in Patients With Stage I Non-Small Cell Lung Cancer. [Journal Article]
- TCTechnol Cancer Res Treat 2018 Jan 01; 17:1533033818794934
- CONCLUSIONS: The results indicated that fluorodeoxyglucose uptake in the lung parenchyma, expressed as the tissue fraction-corrected standardized uptake value, was an independent prognostic factor in patients with stage I non-small cell lung cancer who have received stereotactic body radiation therapy.
New Search Next
- Arthritis Mutilans in Systemic Sclerosis. [Journal Article]
- ARArthritis Rheumatol 2018 Sep 17
- A 40-year-old gentleman was diagnosed with anti-topoisomerase-I antibody positive diffuse cutaneous systemic sclerosis (SSc). Raynaud's phenomenon, diffuse skin sclerosis and severe interstitial lung...
A 40-year-old gentleman was diagnosed with anti-topoisomerase-I antibody positive diffuse cutaneous systemic sclerosis (SSc). Raynaud's phenomenon, diffuse skin sclerosis and severe interstitial lung disease (ILD) were the onset features causing digital ischemia, disability and dyspnea. He subsequently developed inflammatory polyarthritis (IA) with hands and wrists involvement. His brother had psoriasis. Physical examination showed fingertip pitting scars, subcutaneous calcinosis, skin sclerosis with hyper- and hypopigmentation, flexion and extension contractures and shortened fingers (Figure 1.A). This article is protected by copyright. All rights reserved.