Cross-talk between IL-6 trans-signaling and AIM2 inflammasome/IL-1β axes bridge innate immunity and epithelial apoptosis to promote emphysema.

Pulmonary emphysema is associated with dysregulated innate immune responses that promote chronic pulmonary inflammation and alveolar apoptosis, culminating in lung destruction. However, the molecular regulators of innate immunity that promote emphysema are ill-defined. Here, we investigated whether innate immune inflammasome complexes, comprising the adaptor ASC, Caspase-1 and specific pattern recognition receptors (PRRs), promote the pathogenesis of emphysema.

Oncogenic dependency on STAT3 serine phosphorylation in KRAS mutant lung cancer.

The oncogenic potential of the latent transcription factor signal transducer and activator of transcription (STAT)3 in many human cancers, including lung cancer, has been largely attributed to its nuclear activity as a tyrosine-phosphorylated (pY site) transcription factor. By contrast, an alternate mitochondrial pool of serine phosphorylated (pS site) STAT3 has been shown to promote tumourigenesis by regulating metabolic processes, although this has been reported in only a restricted number of mutant RAS-addicted neoplasms. Therefore, the involvement of STAT3 serine phosphorylation in the pathogenesis of most cancer types, including mutant KRAS lung adenocarcinoma (LAC), is unknown.

Laparoscopic Fundoplication Using the Excluded Stomach as a Novel Management Option for Refractory Bile Reflux Following One Anastomosis Gastric Bypass (OAGB).

Background: One anastomosis gastric bypass (OAGB) is now a mainstream bariatric procedure. Refractory gastroesophageal reflux is a significant complication following OAGB, and conversion to Roux-en-Y has long been the treatment of choice for this issue. Strengthening the lower esophageal sphincter by Nissen fundoplication (NF) has been reported as an effective anti-reflux surgery.

ADAM17 Deficiency Protects against Pulmonary Emphysema.

Pulmonary emphysema is the major debilitating component of chronic obstructive pulmonary disease (COPD), which is a leading cause of morbidity and mortality worldwide. The ADAM17 (A disintegrin and metalloproteinase 17) protease mediates inflammation via ectodomain shedding of numerous proinflammatory cytokines, cytokine receptors, and adhesion molecules; however, its role in the pathogenesis of emphysema and COPD is poorly understood. This study aims to define the role of the protease ADAM17 in the pathogenesis of pulmonary emphysema.

Pirfenidone: Molecular Mechanisms and Potential Clinical Applications in Lung Disease.

Pirfenidone (PFD) is a pharmacological compound with therapeutic efficacy in idiopathic pulmonary fibrosis. It has been chiefly characterized as an antifibrotic agent, although it was initially developed as an antiinflammatory compound because of its ability to diminish the accumulation of inflammatory cells and cytokines. Despite recent studies that have elucidated key mechanisms, the precise molecular activities of PFD remain incompletely understood.

The ADAM17 protease promotes tobacco smoke carcinogen-induced lung tumorigenesis.

Lung cancer is the leading cause of cancer-related mortality, with most cases attributed to tobacco smoking, in which nicotine-derived nitrosamine ketone (NNK) is the most potent lung carcinogen. The ADAM17 protease is responsible for the ectodomain shedding of many pro-tumorigenic cytokines, growth factors and receptors, and therefore is an attractive target in cancer. However, the role of ADAM17 in promoting tobacco smoke carcinogen-induced lung carcinogenesis is unknown.

ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer.

Oncogenic mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC In genetically engineered and xenograft (human cell line and patient-derived) -driven LAC models, the specific blockade of ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro-tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via the ERK1/2 MAPK pathway.

Lung Diseases.

Inflammasomes are large innate cytoplasmic complexes that play a major role in promoting inflammation in the lung in response to a range of environmental and infectious stimuli. Inflammasomes are critical for driving acute innate immune responses that resolve infection and maintain tissue homeostasis. However, dysregulated or excessive inflammasome activation can be detrimental.

Tissue Processing for Stereological Analyses of Lung Structure in Chronic Obstructive Pulmonary Disease.

Quantitative data on lung structure, such as volume, surface area and length, are used for assessment of the functional performance of the lung during normal development and inflammatory-related diseases such as chronic obstructive pulmonary disorder (COPD), and carcinogenesis, in animal models. Stereology is considered as the gold standard to obtain quantitative data on lung structure, with a key advantage being to quantify irregular three-dimensional structures on the basis of measurement made on two-dimensional sections. Therefore, preservation of original tissue dimensions without shrinkage is vital for stereology.

Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism.

Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation.

Deoxyribonuclease 1 reduces pathogenic effects of cigarette smoke exposure in the lung.

Our aim was to investigate if deoxyribonuclease (DNase) 1 is a potential therapeutic agent to reduce pathogenic effects of cigarette smoke exposure in the lung. Cigarette smoke causes protease imbalance with excess production of proteases, which is a key process in the pathogenesis of emphysema. The mechanisms responsible for this effect are not well-defined.

Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.

Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130 knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis.

Transcriptional regulation of inflammasome-associated pattern recognition receptors, and the relevance to disease pathogenesis.

Over the last decade it has emerged that inflammasome complexes provide a pivotal platform for the host innate immune system to respond to exogenous infectious microbes (viruses, bacteria, fungi) and non-infectious environmental agents (cigarette smoke, pollution), as well as endogenous "danger" signals. Upon the canonical activation of inflammasomes, a key effector function is to catalyze, via caspase-1, the maturation of the potent pro-inflammatory cytokines interleukin (IL)-1β and IL-18, which, in addition to chronic inflammatory responses have also been intimately linked to the inflammatory form of lytic cell death, pyroptosis. However, recent evidence suggests that inflammasomes exhibit marked pleiotropism beyond their canonical functions, whereby their activation can also influence a large number of cellular responses including proliferation, apoptosis, autophagy and metabolism.

Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema.

Rationale: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R.

Objectives: To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema.

IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis.

Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130(F/F) (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRAS-driven lung tumorigenesis.

Differential involvement of gp130 signalling pathways in modulating tobacco carcinogen-induced lung tumourigenesis.

Interleukin (IL)-6 family cytokines signal exclusively via the gp130 coreceptor, and are implicated in smoking-associated lung cancer, the most lethal cancer worldwide. However, the role of gp130 signalling pathways in transducing the carcinogenic effects of tobacco-related compounds is ill-defined. Here, we report that lung tumourigenesis induced by the potent tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (Nicotine-derived Nitrosamine Ketone; NNK) is suppressed in gp130(F/F) knock-in mice characterized by the contrasting gp130-dependant hypoactivation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) and phosphatidylinositol 3-kinase/Akt, and hyperactivation of signal transducer and activator of transcription (STAT)3 signalling cascades.

IL-6/Stat3-driven pulmonary inflammation, but not emphysema, is dependent on interleukin-17A in mice.

Background And Objective: Pulmonary emphysema is linked to T cell-mediated autoimmune inflammation, although the pathogenic role of specific pro-inflammatory cytokines remains unclear. The Th17 type response, characterized by the production of the cytokine interleukin (IL)-17A, is modulated in part by the IL-6/signal transducer and activator of transcription (Stat)3 signalling axis and is associated with numerous autoimmune diseases. We therefore evaluated a causal role for IL-17A in the IL-6-driven gp130(F/F) mouse model for spontaneous pulmonary inflammation and emphysema.

Non-essential role for TLR2 and its signaling adaptor Mal/TIRAP in preserving normal lung architecture in mice.

Myeloid differentiation factor 88 (MyD88) and MyD88-adaptor like (Mal)/Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) play a critical role in transducing signals downstream of the Toll-like receptor (TLR) family. While genetic ablation of the TLR4/MyD88 signaling axis in mice leads to pulmonary cell death and oxidative stress culminating in emphysema, the involvement of Mal, as well as TLR2 which like TLR4 also signals via MyD88 and Mal, in the pathogenesis of emphysema has not been studied. By employing an in vivo genetic approach, we reveal here that unlike the spontaneous pulmonary emphysema which developed in Tlr4(-/-) mice by 6 months of age, the lungs of Tlr2(-/-) mice showed no physiological or morphological signs of emphysema.

Deregulated Stat3 signaling dissociates pulmonary inflammation from emphysema in gp130 mutant mice.

Interleukin (IL)-6 is a potent immunomodulatory cytokine that is associated with emphysema, a major component of chronic obstructive pulmonary disease (COPD). IL-6 signaling via the gp130 coreceptor is coupled to multiple signaling pathways, especially the latent transcription factor signal transducer and activator of transcription (Stat)3. However, the pathological role of endogenous gp130-dependent Stat3 activation in emphysema is ill defined.

Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice.

The IL-6 cytokine family, which signals via the shared gp130 coreceptor, is linked with the pathogenesis of emphysema. However, the definitive mechanisms by which these cytokines cause emphysema remain ill-defined. We took an in vivo genetic complementation approach to identify the specific IL-6 cytokine family members and gp130-regulated cellular processes that cause emphysema.

Tumor cell response to synchrotron microbeam radiation therapy differs markedly from cells in normal tissues.

Purpose: High-dose synchrotron microbeam radiation therapy (MRT) can be effective at destroying tumors in animal models while causing very little damage to normal tissues. The aim of this study was to investigate the cellular processes behind this observation of potential clinical importance.

Methods And Materials: MRT was performed using a lattice of 25 mum-wide, planar, polychromatic, kilovoltage X-ray microbeams, with 200-microm peak separation.

Hormonal regulation of male germ cell development.

Over the past five decades, intense research using various animal models, innovative technologies notably genetically modified mice and wider use of stereological methods, unique agents to modulate hormones, genomic and proteomic techniques, have identified the cellular sites of spermatogenesis, that are regulated by FSH and testosterone. It has been established that testosterone is essential for spermatogenesis, and also FSH plays a valuable role. Therefore understanding the basic mechanisms by which hormones govern germ cell progression are important steps towards improved understating of fertility regulation in health diseases.

Pathways involved in testicular germ cell apoptosis in immature rats after FSH suppression.

FSH is a key regulator of testis function, required for the establishment of full complements of Sertoli and germ cells during postnatal testis development and for the maintenance of spermatogenesis in the adult. FSH plays an important role in germ cell survival rather than proliferation, in the window between 14 and 18 days of testicular development, which coincides with the cessation of Sertoli cell proliferation and the onset of germ cell meiosis during the first wave of spermatogenesis. This study aimed to identify the pathway(s) of apoptosis regulated by changes in FSH levels in 14 - to 18-day-old rats, using a model of in vivo FSH suppression by passive immunoneutralization with a rat anti-FSH antibody.

Gonadotrophins regulate germ cell survival, not proliferation, in normal adult men.

Background: Gonadotrophins support spermatogenesis via poorly understood mechanisms. We aimed to determine the effect of FSH/LH suppression in regulating germ cell apoptosis and proliferation in normal fertile men.

Methods: Testicular tissues were obtained after gonadotrophin suppression induced by testosterone alone or combined with depot medroxyprogesterone acetate for 2 or 6 weeks and an untreated group of men (referred to as 'normal men') served as controls (n = 5 or 10 men per group).

Follicle-stimulating hormone affects spermatogonial survival by regulating the intrinsic apoptotic pathway in adult rats.

Follicle-stimulating hormone plays a key role in spermatogonial development in adult rats via poorly understood mechanisms. We aimed to identify the role of this hormone in the regulation of germ cell apoptosis and proliferation in adult rats by suppression of FSH action following passive immunoneutralization with a rat FSH antibody for 4 and 7 days. Apoptosis and proliferation were identified by TUNEL and proliferating cell nuclear antigen labeling methods, respectively.