Rheumatoid Arthritis-Associated Interstitial Lung Disease: Diagnostic Dilemma

Interstitial lung disease (ILD) is an increasingly recognized complication of rheumatoid arthritis (RA) contributing to significantly increased morbidity and mortality. Diagnosis can be challenging since patients are unlikely to report dyspnea due to an overall decrease in physical activity with advanced arthritic symptoms. Additionally, infections, drug toxicity, and environmental toxins can mimic ILD, creating significant diagnostic dilemmas for the clinician. In this paper we will explore an effective clinical algorithm for the diagnosis of RA-ILD. We will also discuss features of drug-related toxicities, infections, and environmental toxins that comprise the main entities in the differential diagnosis of RA-ILD. Finally, we will explore the known and experimental treatment options that may have some benefit in the treatment of RA-ILD

Identification of the Molecular Mechanism by which TLR Ligation and IFN-γ Synergize to Induce Mig

Monokine Induced by Interferon- (MIG), a CXC chemokine, is a potent inducer of T-cell chemotaxis and activation and has been implicated in the host response to viral infections and tumor immunity as well as in the pathogenesis of autoimmunity and transplant rejection. Although it is known that the Toll-Like Receptor-4 (TLR-4) ligand LPS synergizes with IFN-γ to induce MIG expression in macrophages, the molecular mechanisms responsible for the synergy have yet to be elucidated. We determined that the marked synergy between LPS and IFN-γ on MIG mRNA expression in mouse macrophages is a result of LPS-induced NF-κB and IFN-γ-induced STAT. The synergy was not dependent on new protein synthesis, was independent of TNF-α, and occurred at the level of gene transcription. We identified 2 NF-κB sites located at -154 and -129 of the MIG promoter proximal to the -responsive element that mediated this effect. Finally, we demonstrated that other TLR ligands (zymosan, double stranded RNA and CpG) synergized with IFN-γ to induce MIG in an NF-κB dependent fashion. These data emphasize the ability of bacterial and viral products to activate/modify immune responses and promote adaptive T cell immunity through the NF-κB pathway

Anti-oxidant inhibition of hyaluronan fragment-induced inflammatory gene expression

<p>Abstract</p> <p>Background</p> <p>The balance between reactive oxygen species (ROS) and endogenous anti-oxidants is important in maintaining healthy tissues. Excessive ROS states occur in diseases such as ARDS and Idiopathic Pulmonary Fibrosis. Redox imbalance breaks down the extracellular matrix component hyaluronan (HA) into fragments that activate innate immune responses and perpetuate tissue injury. HA fragments, via a TLR and NF-κB pathway, induce inflammatory gene expression in macrophages and epithelial cells. NAC and DMSO are potent anti-oxidants which may help balance excess ROS states.</p> <p>Methods</p> <p>We evaluated the effect of H₂O₂, NAC and DMSO on HA fragment induced inflammatory gene expression in alveolar macrophages and epithelial cells.</p> <p>Results</p> <p>NAC and DMSO inhibit HA fragment-induced expression of TNF-α and KC protein in alveolar and peritoneal macrophages. NAC and DMSO also show a dose dependent inhibition of IP-10 protein expression, but not IL-8 protein, in alveolar epithelial cells. In addition, H₂O₂synergizes with HA fragments to induce inflammatory genes, which are inhibited by NAC. Mechanistically, NAC and DMSO inhibit HA induced gene expression by inhibiting NF-κB activation, but NAC had no influence on HA-fragment-AP-1 mediated gene expression.</p> <p>Conclusion</p> <p>ROS play a central role in a pathophysiologic "vicious cycle" of inflammation: tissue injury generates ROS, which fragment the extracellular matrix HA, which in turn synergize with ROS to activate the innate immune system and further promote ROS, HA fragment generation, inflammation, tissue injury and ultimately fibrosis. The anti-oxidants NAC and DMSO, by inhibiting the HA induced inflammatory gene expression, may help re-balance excessive ROS induced inflammation.</p

Pulmonary Vaccination as a Novel Treatment for Lung Fibrosis

Pulmonary fibrosis is an untreatable, uniformly fatal disease of unclear etiology that is the result of unremitting chronic inflammation. Recent studies have implicated bone marrow derived fibrocytes and M2 macrophages as playing key roles in propagating fibrosis. While the disease process is characterized by the accumulation of lymphocytes in the lung parenchyma and alveolar space, their role remains unclear. In this report we definitively demonstrate the ability of T cells to regulate lung inflammation leading to fibrosis. Specifically we demonstrate the ability of intranasal vaccinia vaccination to inhibit M2 macrophage generation and fibrocyte recruitment and hence the accumulation of collagen and death due to pulmonary failure. Mechanistically, we demonstrate the ability of lung Th1 cells to prevent fibrosis as vaccinia failed to prevent disease in Rag−/− mice or in mice in which the T cells lacked IFN-γ. Furthermore, vaccination 3 months prior to the initiation of fibrosis was able to mitigate the disease. Our findings clearly demonstrate the role of T cells in regulating pulmonary fibrosis as well as suggest that vaccinia-induced immunotherapy in the lung may prove to be a novel treatment approach to this otherwise fatal disease

Re-Imagining School Feeding : A High-Return Investment in Human Capital and Local Economies

Analysis shows that a quality education, combined with a guaranteed package of health and nutrition interventions at school, such as school feeding, can contribute to child and adolescent development and build human capital. School feeding programs can help get children into school and help them stay there, increasing enrollment and reducing absenteeism. Once children are in the classroom, these programs can contribute to their learning by avoiding hunger and enhancing cognitive abilities. The benefits are especially great for the poorest and most disadvantaged children. As highlighted in the World Bank’s 2018 World Development Report (World Bank 2018), countries need to prioritize learning, not just schooling. Children must be healthy, not hungry, if they are to match learning opportunities with the ability to learn. In the most vulnerable communities, nutrition-sensitive school meals can offer children a regular source of nutrients that are essential for their mental and physical development. And for the growing number of countries with a “double burden” of undernutrition and emerging obesity problems, well-designed school meals can help set children on the path toward more healthy diets. In Latin America, for example, where there is a growing burden of noncommunicable diseases (NCDs), school feeding programs are a key intervention in reducing undernutrition and promoting healthy diet choices. Mexico’s experience reducing sugary beverages in school cafeterias, for example, was found to be beneficial in advancing a healthy lifestyle. A large trial of school-based interventions in China also found that nutritional or physical activity interventions alone are not as effective as a joint program that combines nutritional and educational interventions. In poor communities, economic benefits from school feeding programs are also evident—reducing poverty by boosting income for households and communities as a whole. For families, the value of meals in school is equivalent to about 10 percent of a household’s income. For families with several children, that can mean substantial savings. As a result, school feeding programs are often part of social safety nets in poor countries, and they can be a stable way to reliably target pro-poor investments into communities, as well as a system that can be scaled up rapidly to respond to crises. There are also direct economic benefits for smallholder farmers in the community. Buying local food creates stable markets, boosting local agriculture, impacting rural transformation, and strengthening local food systems. In Brazil, for example, 30 percent of all purchases for school feeding come from smallholder agriculture (Drake and others 2016). These farmers are oftentimes parents with schoolchildren, helping them break intergenerational cycles of hunger and poverty. Notably, benefits to households and communities offer important synergies. The economic growth in poor communities helps provide stability and better-quality education and health systems that promote human capital. At the same time, children and adolescents grow up to enjoy better employment and social opportunities as their communities grow