Systemic Inhibition of NF-κB Activation Protects from Silicosis

Background: Silicosis is a complex lung disease for which no successful treatment is available and therefore lung transplantation is a potential alternative. Tumor necrosis factor alpha (TNFα) plays a central role in the pathogenesis of silicosis. TNFα signaling is mediated by the transcription factor, Nuclear Factor (NF)-κB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-κB activation represents a potential therapeutic strategy for silicosis. Methods/Findings: In the present work we evaluated the lung transplant database (May 1986-July 2007) at the University of Pittsburgh to study the efficacy of lung transplantation in patients with silicosis (n = 11). We contrasted the overall survival and rate of graft rejection in these patients to that of patients with idiopathic pulmonary fibrosis (IPF, n = 79) that was selected as a control group because survival benefit of lung transplantation has been identified for these patients. At the time of lung transplantation, we found the lungs of silica-exposed subjects to contain multiple foci of inflammatory cells and silicotic nodules with proximal TNFα expressing macrophage and NF-κB activation in epithelial cells. Patients with silicosis had poor survival (median survival 2.4 yr; confidence interval (CI): 0.16-7.88 yr) compared to IPF patients (5.3 yr; CI: 2.8-15 yr; p = 0.07), and experienced early rejection of their lung grafts (0.9 yr; CI: 0.22-0.9 yr) following lung transplantation (2.4 yr; CI:1.5-3.6 yr; p<0.05). Using a mouse experimental model in which the endotracheal instillation of silica reproduces the silica-induced lung injury observed in humans we found that systemic inhibition of NF-κB activation with a pharmacologic inhibitor (BAY 11-7085) of IκBα phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IκBα mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica. Conclusions: Although limited by its size, our data support that patients with silicosis appear to have poor outcome following lung transplantation. Experimental data indicate that while the systemic inhibition of NF-κB protects from silica-induced lung injury, epithelial cell specific NF-κB inhibition appears to aggravate the outcome of experimental silicosis. © 2009 Di Giuseppe et al

Particulate air pollution, systemic oxidative stress, inflammation, and atherosclerosis

Air pollution has been associated with significant adverse health effects leading to increased overall morbidity and mortality of worldwide significance. Epidemiological studies have shown that the largest portion of air pollution-related mortality is due to cardiovascular diseases, predominantly those of ischemic nature. Human studies suggest an association with atherosclerosis and increasing experimental animal data support that this association is likely to be causal. While both gasses and particles have been linked to detrimental health effects, more evidence implicates the particulate matter (PM) components as major responsible for a large portion of the proatherogenic effects. Multiple experimental approaches have revealed the ability of PM components to trigger and/or enhance free radical reactions in cells and tissues, both ex vivo as well as in vivo. It appears that exposure to PM leads to the development of systemic prooxidant and proinflammatory effects that may be of great importance in the development of atherosclerotic lesions. This article reviews the epidemiological studies, experimental animal, and cellular data that support the association of air pollutants, especially the particulate components, with systemic oxidative stress, inflammation, and atherosclerosis. It also reviews the use of transcriptomic studies to elucidate molecular pathways of importance in those systemic effects

Impact of the number of aspiration risk factors on mortality and recurrence in community-onset pneumonia

Shingo Noguchi,1 Kazuhiro Yatera,1 Tatsuji Kato,2 Yasuo Chojin,2 Yoshihisa Fujino,3 Kentaro Akata,1 Toshinori Kawanami,1 Noriho Sakamoto,4 Hiroshi Mukae4 1Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; 2Department of Respiratory Medicine, Tobata Kyoritsu Hospital, Kitakyushu, Japan; 3Department of Preventive Medicine and Community Health, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; 4Department of Respiratory Medicine, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan Introduction: The clinical significance of the number of aspiration risk factors in patients with pneumonia is unknown as yet. In the present study, we clarify the significance of the number of aspiration risk factors for mortality and recurrence in pneumonia patients.Methods: This study included 322 patients hospitalized with pneumonia between December 2014 and June 2016. We investigated associations between the number of aspiration risk factors present (orientation disturbance, bedridden, chronic cerebrovascular disease, dementia, sleeping medications and gastroesophageal disease) and 30-day and 6-month mortality, and pneumonia recurrence within 30 days.Results: Patients were categorized by number of risk factors present into groups of 0&ndash;1, 2, 3, and 4 or more. Of a total of 322 patients, 93 (28.9%) had 0&ndash;1 risk factors, 112 (34.8%) had 2, 88 (27.3%) had 3, and 29 (9.0%) had 4 or more risk factors. The percentages of patients with recurrence of pneumonia were 13.0%, 33.0%, 43.2%, and 54.2% in the 0&ndash;1, 2, 3, and 4 or more risk factor groups, respectively. The percentages of patients with 30-day mortality were 2.2%, 5.4%, 11.4%, and 24.1%, and those of patients with 6-month mortality were 6.6%, 24.5%, 30.7%, and 50.0%, in the 0&ndash;1, 2, 3, and 4 or more risk factor groups, respectively.Conclusions: The number of aspiration risk factors was associated with increases in both mortality and recurrence in pneumonia patients. Therefore, in clinical practice, physicians should consider not only the presence of aspiration risks but also the number of aspiration risk factors in these patients. Keywords: aspiration pneumonia, bedridden, dementia, sleeping medications, mortality, recurrence of pneumonia&nbsp

Bacteriological incidence in pneumonia patients with pulmonary emphysema: a bacterial floral analysis using the 16S ribosomal RNA gene in bronchoalveolar lavage fluid

Keisuke Naito,1 Kei Yamasaki,1 Kazuhiro Yatera,1 Kentaro Akata,1 Shingo Noguchi,1 Toshinori Kawanami,1 Kazumasa Fukuda,2 Takashi Kido,1 Hiroshi Ishimoto,3 Hiroshi Mukae3 1Department of Respiratory Medicine, 2Department of Microbiology, University of Occupational and Environmental Health, Japan, Kitakyushu City, Fukuoka, 3Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki City, Nagasaki, Japan Abstract: Pulmonary emphysema is an important radiological finding in chronic obstructive pulmonary disease patients, but bacteriological differences in pneumonia patients according to the severity of emphysematous changes have not been reported. Therefore, we evaluated the bacteriological incidence in the bronchoalveolar lavage fluid (BALF) of pneumonia patients using cultivation and a culture-independent molecular method. Japanese patients with community-acquired pneumonia (83) and healthcare-associated pneumonia (94) between April 2010 and February 2014 were evaluated. The BALF obtained from pneumonia lesions was evaluated by both cultivation and a molecular method. In the molecular method, ~600 base pairs of bacterial 16S ribosomal RNA genes in the BALF were amplified by polymerase chain reaction, and clone libraries were constructed. The nucleotide sequences of 96 randomly selected colonies were determined, and a homology search was performed to identify the bacterial species. A qualitative radiological evaluation of pulmonary emphysema based on chest computed tomography (CT) images was performed using the Goddard classification. The severity of pulmonary emphysema based on the Goddard classification was none in 47.4% (84/177), mild in 36.2% (64/177), moderate in 10.2% (18/177), and severe in 6.2% (11/177). Using the culture-independent molecular method, Moraxella catarrhalis was significantly more frequently detected in moderate or severe emphysema patients than in patients with no or mild emphysematous changes. The detection rates of Haemophilus influenzae and Pseudomonas aeruginosa were unrelated to the severity of pulmonary emphysematous changes, and Streptococcus species &ndash; except for the S. anginosus group and S. pneumoniae &ndash; were detected more frequently using the molecular method we used for the BALF of patients with pneumonia than using culture methods. Our findings suggest that M. catarrhalis is more frequently detected in pneumonia patients with moderate or severe emphysema than in those with no or mild emphysematous changes on chest CT. M. catarrhalis may play a major role in patients with pneumonia complicating severe pulmonary emphysema. Keywords: clone library method, chronic obstructive pulmonary disease, Goddard classification, molecular method, microflora, phylotype, Moraxella catarrhali

Supplementary Material for: The Importance of Obligate Anaerobes and the Streptococcus anginosus Group in Pulmonary Abscess: A Clone Library Analysis Using Bronchoalveolar Lavage Fluid

<i>Background:</i> Appropriate antibiotic use reduces the mortality of patients with lung abscess; however, 40-60% of the bacterial etiologies in these patients have remained unknown with the culture methods. Obligate anaerobes and the <i>Streptococcus anginosus</i> group are common pathogens in lung abscess, but a precise evaluation of these bacteria by ordinary culture methods seems to be difficult due to upper respiratory tract contamination. <i>Objectives:</i> The aim of this study was to assess the microbiota of lung abscess by bronchoalveolar lavage fluid (BALF) using the molecular method in comparison to culture methods. <i>Methods:</i> BALF samples obtained from the affected lesions and sputum samples of 59 patients with lung abscess were evaluated. The microbiota in BALF was analyzed according to the molecular method using the 16S ribosomal RNA gene. <i>Results:</i> Fifty-six of the 59 BALF samples were positive in polymerase chain reaction analysis. <i>Fusobacterium</i> spp. (23.7%) were most frequently detected, followed by the <i>S. anginosus</i> group (15.3%), as the predominant phylotypes. Obligate anaerobes were detected in 42.4% of the BALF specimens as the predominant phylotypes, whereas the detection rate of obligate anaerobes was 13.6% by culture methods using BALF. In addition, the detection rate among those patients in whom the phylotype of obligate anaerobes was detected in >5% of the lung microbiota according to the molecular method was 86.5% in the ‘mixed-bacterial' infection group. <i>Conclusions:</i> The findings by the molecular method suggest that obligate anaerobes play important roles in the pathogenesis of lung abscess and provide additional bacterial information regarding conventional culture methods