Potential Role of the Inflammasome-Derived Inflammatory Cytokines in Pulmonary Fibrosis

Pulmonary fibrosis is a progressive, disabling disease with mortality rates that appear to be increasing in the western population, including the USA. There are over 140 known causes of pulmonary fibrosis as well as many unknown causes. Treatment options for this disease are limited due to poor understanding of the molecular mechanisms of the disease progression. However, recent progress in inflammasome research has greatly contributed to our understanding of its role in inflammation and fibrosis development. The inflammasome is a multiprotein complex that is an important component of both the innate and adaptive immune systems. Activation of proinflammatory cytokines following inflammasome assembly, such as IL-1β and IL-18, has been associated with development of PF. In addition, components of the inflammasome complex itself, such as the adaptor protein ASC have been associated with PF development. Recent evidence suggesting that the fibrotic process can be reversed via blockade of pathways associated with inflammasome activity may provide hope for future drug strategies. In this paper we will give an introduction to pulmonary fibrosis and its known causes. In addition, we will discuss the importance of the inflammasome in the development of pulmonary fibrosis as well as discuss potential future treatment options

Role of Lysosomes in Silica-Induced Inflammasome Activation and Inflammation in Absence of MACRO

MARCO is the predominant scavenger receptor for recognition and binding of silica particles by alveolar macrophages (AM). Previously, it was shown that mice null for MARCO have a greater inflammatory response to silica, but the mechanism was not described. The aim of this study was to determine the relationship between MARCO and NLRP3 inflammasome activity. Silica increased NLRP3 inflammasome activation and release of the proinflammatory cytokine, IL-1b, to a greater extent in MARCO-/- AM compared to wild type (WT) AM. Furthermore, in MARCO-/- AM there was greater cathepsin B release from phagolysosomes, Caspase-1 activation, and acid sphingomyelinase activity compared toWT AM, supporting the critical role played by lysosomal membrane permeabilization (LMP) in triggering silica-induced inflammation.The difference in sensitivity to LMP appears to be in cholesterol recycling since increasing cholesterol in AM by treatment with U18666A decreased silica-induced NLRP3 inflammasome activation, and cells lacking MARCO were less able to sequester cholesterol following silica treatment. Taken together, these results demonstrate thatMARCO contributes to normal cholesterol uptake in macrophages; therefore, in the absence ofMARCO, macrophages are more susceptible to a greater inflammatory response by particulates known to cause NLRP3 inflammasome activation and the effect is due to increased LMP

Toxicity of Lunar and Martian Dust Simulants to Alveolar Macrophages Isolated from Human Volunteers

NASA is planning to build a habitat on the Moon and use the Moon as a stepping stone to Mars. JSC-1, an Arizona volcanic ash that has mineral properties similar to lunar soil, is used to produce lunar environments for instrument and equipment testing. NASA is concerned about potential health risks to workers exposed to these fine dusts in test facilities. The potential toxicity of JSC-1 and a Martian soil simulant (JSC-Mars-1, a Hawaiian volcanic ash) was evaluated using human alveolar macrophages (HAM) isolated from volunteers; titanium dioxide and quartz were used as reference dusts. This investigation is a prerequisite to studies of actual lunar dust. HAM were treated in vitro with these test dusts for 24 h; assays of cell viability and apoptosis showed that JSC-1 and TiO2 were comparable, and more toxic than saline control, but less toxic than quartz. HAM treated with JSC-1 or JSC-Mars 1 showed a dose-dependent increase in cytotoxicity. To elucidate the mechanism by which these dusts induce apoptosis, we investigated the involvement of the scavenger receptor (SR). Pretreatment of cells with polyinosinic acid, an SR blocker, significantly inhibited both apoptosis and necrosis. These results suggest HAM cytotoxicity may be initiated by interaction of the dust particles with SR. Besides being cytotoxic, silica is known to induce shifting of HAM phenotypes to an immune active status. The immunomodulatory effect of the simulants was investigated. Treatment of HAM with either simulant caused preferential damage to the suppressor macrophage subpopulation, leading to a net increase in the ratio of activator (RFD1+) to suppressor (RFD1+7+) macrophages, a result similar to treatment with silica. It is recommended that appropriate precautions be used to minimize exposure to these fine dusts in large-scale engineering applications

Evolution of the Air Toxics Under the Big Sky Program

As a yearlong exploration of air quality and its relation to respiratory health, the “Air Toxics Under the Big Sky” program offers opportunities for students to learn and apply science process skills through self-designed inquiry-based research projects conducted within their communities. The program follows a systematic scope and sequence designed to first lay a strong foundation, followed by activities intended to expand understanding, and ending with a final step aimed at achieving retention of content and principles learned. The foundation consists of content regarding environmental health sciences and human health. The next level guides students during their independent study projects as they test their hypotheses, analyze results, and draw conclusions. The final step requires these junior researchers to share their findings with others in some type of culminating event, with the most prominent being a high school symposium held at the conclusion of the school year. This article describes the evolution of the Air Toxics Under the Big Sky program since its inception in 2003

The Big Sky Model: A Regional Collaboration for Participatory Research on Environmental Health in the Rural West

As an innovative community-based framework for science learning, the Big Sky Model is guiding high school and tribal college students from rural areas of Montana and Idaho in their understanding of chemical, physical, and environmental health concepts in the context of their own homes, schools, and communities. Students participate in classroom lessons and continue with systematic inquiry through actual field research to investigate a pressing, real-world issue: understanding the complex links between poor air quality and respiratory health outcomes. This article provides background information, outlines the procedure for implementing the model, and discusses its effectiveness as demonstrated through various evaluation tools

The Power of the Symposium: Impacts from Students\u27 Perspectives

The Air Toxics under the Big Sky program developed at the University of Montana is a regional outreach and education initiative that offers a yearlong exploration of air quality and its relation to respiratory health. The program was designed to connect university staff and resources with rural schools enabling students to learn and apply science process skills through self-designed research projects conducted within their communities. As part of the program, students develop and conduct independent projects, then share their findings at the conclusion of the school year in some type of interactive capstone experience, the most prominent being a high school symposium held at The University of Montana campus. Student feedback collected through a carefully controlled evaluation program suggest that the annual symposium as the culminating event is a critical component of the Air Toxics Under the Big Sky program, and a valuable learning experience as many of the students go on to post-secondary education. AcknowledgmentsThe authors wish to thank all the students who have participated in the Air Toxics Under the Big Sky Program, with our special gratitude toward the many dedicated teachers who have made its implementation so successful and rewarding. Funding for this project was provided by the Toyota USA Foundation and by a Science Education Partnership Award, Grant Number R25 RR020432, from the National Center for Research Resources, a component of the National Institutes of Health. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the officials views of our funding sponsors

Synthesis, characterization, and bioactivity of carboxylic acid-functionalized titanium dioxide nanobelts

Background: Surface modification strategies to reduce engineered nanomaterial (ENM) bioactivity have been used successfully in carbon nanotubes. This study examined the toxicity and inflammatory potential for two surface modifications (humic acid and carboxylation) on titanium nanobelts (TNB). Methods: The in vitro exposure models include C57BL/6 alveolar macrophages (AM) and transformed human THP-1 cells exposed to TNB for 24 hrs in culture. Cell death and NLRP3 inflammasome activation (IL-1β release) were monitored. Short term (4 and 24 hr) in vivo studies in C57BL/6, BALB/c and IL-1R null mice evaluated inflammation and cytokine release, and cytokine release from ex vivo cultured AM. Results: Both in vitro cell models suggest that the humic acid modification does not significantly affect TNB bioactivity, while carboxylation reduced both toxicity and NLRP3 inflammasome activation. In addition, short term in vivo exposures in both C57BL/6 and IL-1R null mouse strains demonstrated decreased markers of inflammation, supporting the in vitro finding that carboxylation is effective in reducing bioactivity. TNB instillations in IL-1R null mice demonstrated the critical role of IL-1β in initiation of TNB-induced lung inflammation. Neutrophils were completely absent in the lungs of IL-1R null mice instilled with TNB for 24 hrs. However, the cytokine content of the IL-1R null mice lung lavage samples indicated that other inflammatory agents, IL-6 and TNF-α were constitutively elevated indicating a potential compensatory inflammatory mechanism in the absence of IL-1 receptors. Conclusions: Taken together, the data suggests that carboxylation, but not humic acid modification of TNB reduces, but does not totally eliminate bioactivity of TNB, which is consistent with previous studies of other long aspect ratio nanomaterials such as carbon nanotubes