Lung | EPFL Graph Search

The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of the heart. Their function in the respiratory system is to extract oxygen from the air and transfer it into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere, in a process of gas exchange. The pleurae, which are thin, smooth, and moist, serve to reduce friction between the lungs and chest wall during breathing, allowing for easy and effortless movements of the lungs. Respiration is driven by different muscular systems in different species. Mammals, reptiles and birds use their different muscles to support and foster breathing. In earlier tetrapods, air was driven into the lungs by the pharyngeal muscles via buccal pumping, a mechanism still seen in amphibians. In humans, the main muscle of respiration that dri

Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis

Eva Sabrina Gollwitzer, Nicola Harris, Benjamin John Marsland

Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein-coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.

Nature Publishing Group2014

The interplay between the VEGF-C/VEGFR-3 axis and CCL21/CCR7 axis in tumor cell invasion

Amine Issa

There are two main routes for tumor spread and metastasis, the blood vasculature and the lymphatic system. A wide range of human carcinomas, including lung, colon and breast cancer, spread to distant sites via the lymphatic system. Preclinical and clinical studies have demonstrated a positive correlation between the incidence of lymph node metastasis and the secretion of vascular endothelial growth factor-C (VEGF-C) by tumor cells. Indeed, VEGF-C is critical for the formation of new lymphatic vessels in a process called lymphangiogenesis, suggesting this mechanism as the main "escape route" for tumor cells. However, many studies have failed to identify functional lymphatic vessels inside tumors, and much research has demonstrated that metastasis can occur in the absence of lymphangiogenesis. Furthermore, there is growing evidence that many tumor cells may express vascular endothelial growth factor receptor-3 (VEGFR-3), the primary receptor for VEGF-C, suggesting that autologous VEGFR-3 signaling loops may enhance the invasive and metastatic potential of tumor cells. Other than lymphangiogenic factors, the lymphatic homing chemokine receptor CCR7 is strongly correlated to lymph node metastasis, suggesting that tumor cells mimic dendritic cells in sensing and homing to lymphatic vessels and lymph nodes. Potential mechanisms underlying these observations have not been elucidated. Using several in vitro 3D models, we examined the interactions between tumor and lymphatic endothelial cells (LECs) to gain insight into the mechanistic roles of VEGF-C and CCR7-mediated tumor cell invasion towards lymphatics as well as elucidate their potential interplay. All the designed experimental setups utilized a 3D matrix for a more physiologically relevant chemokine and growth factor signaling environment. For example, we designed one culture model where tumor cells are seeded in one gel compartment and lymphatic endothelial cells in a horizontally adjacent one, allowing both cell types to establish contact through soluble mediators without being initially mixed while simultaneously allowing direct visualization of their interactions. We first demonstrated that receptor expression patterns by cells are strongly influenced by the extracellular matrix (ECM). Indeed, while we failed to detect tumor expression of VEGFR-3 in 2D conditions, we found both expression and phosphorylation of VEGFR-3 in three of four tumor cell lines tested. Furthermore, in the three VEGFR-3 positive cell lines, invasive capacity and chemoattraction towards lymphatics was demonstrated to be dependent on both VEGF-C secretion and CCR7 expression by the tumor cells. We found that VEGF-C could act in both an autocrine manner, by enhancing the migratory and invasive capacity of tumor cells, and in a paracrine manner where it enhances CCL21 secretion by LECs to promote the chemoinvasion of tumor cells via CCL21 secretion. The same mechanism was also tested in vivo by injecting VEGF-C into mouse skin: VEGF-C, but not saline nor VEGF-A, caused marked upregulation of CCL21 associated with lymphatic vessels. In this way, VEGF-C and CCR7 act synergistically to promote the invasive phenotype of tumor cells. Additionally, we uncovered a new and critical role for VEGFR-3 on mammary epithelial cells. We demonstrated that the receptor is involved in epithelial tubulogenesis in a collagen matrix, and furthermore, it helps to preserve the integrity of a mammary cell layer (since blocking the receptor leads to increased epithelial permeability). In conclusion, this work highlights the importance of the VEGFR-3/VEGF-C and CCR7/CCL21 axis in promoting tumor cell migration and invasion. It also shows that VEGFR-3 may play many roles in the process of tumorigenesis and metastasis.

EPFL2009

Bystander suppression of allergic airway inflammation by lung resident memory CD8+ T cells

Nicola Harris, Benjamin John Marsland

CD8+ memory T cells have recently been recognized as playing a key role in natural immunity against unrelated viral infections, a phenomenon referred to as "heterologous antiviral immunity." We now provide data that the cellular immunological interactions that underlie such heterologous immunity can play an equally important role in regulating T helper 2 immune responses and protecting mucosal surfaces from allergen-induced inflammation. Our data show that CD8+ T cells, either retained in the lung after infection with influenza virus, or adoptively transferred via the intranasal route can suppress allergic airway inflammation. The suppression is mediated by IFN-gamma, which acts to reduce the activation level, T helper 2 cytokine production, airways hyperresponsiveness, and migration of allergen-specific CD4+ T cells into the lung, whereas the systemic and draining lymph node responses remain unchanged. Of note, adoptive transfer of previously activated transgenic CD8+ T cells conferred protection against allergic airway inflammation, even in the absence of specific-antigen. Airway resident CD8+ T cells produced IFN-gamma when directly exposed to conditioned media from activated dendritic cells or the proinflammatory cytokines IL-12 and IL-18. Taken together these data indicate that effector/memory CD8+ T cells present in the airways produce IFN-gamma after inflammatory stimuli, independent of specific-antigen, and as a consequence play a key role in modifying the degree and frequency of allergic responses in the lung.

2004

The interplay between the VEGF-C/VEGFR-3 axis and CCL21/CCR7 axis in tumor cell invasion

Amine Issa

EPFL2009