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

The Prevalence of Human Papillomavirus Infection in Korean Non-Small Cell Lung Cancer Patients

Human papillomavirus (HPV) infection is a co-carcinogen of lung cancer and contributes to its pathogenesis. To evaluate the prevalence of HPV infection, polymerase chain reaction (PCR) was employed to detect HPV 16, 18, and 33 DNA in tumor tissues of 112 patients with non-small cell lung cancer (NSCLC) who underwent curative surgery from Jan. 1995 to Dec. 1998 at Severance Hospital, Seoul, Korea. The patients consisted of 90 men and 22 women. Nineteen patients were under 50 years old (17%), and 92 patients (82%) were smokers. Fifty-three patients had adenocarcinomas, while 59 patients had non-adenocarcinomas. Early stage (I and II) cancer was found in 64 patients (57.1%) and advanced stage (III and IV) found in 48 (42.9%). The prevalence of HPV 16, 18, and 33 were 12 (10.7%), 11 (9.8%), and 37 (33.0%), respectively. Smoking status, sex, and histologic type were not statistically different in the presence of HPV DNA. The presence of HPV 16 was more common in younger patients and HPV 18 was more common in advanced stage patients. This study showed that the prevalence rate of HPV 16 and 18 infections in NSCLC tissue was low, suggesting HPV 16 and 18 infections played a limited role in lung carcinogenesis of Koreans. However, the higher prevalence of HPV 33 infections in Korean lung cancer patients compared to other Asian and Western countries may be important and warrants further investigation

Pathology Case Study: Hemoptysis

This is a pulmonary pathology case study presented by the University of Pittsburgh Department of Pathology in which a 55 year old female has spontaneously occurring hemoptysis. Visitors are given both the microscopic and gross descriptions, radiology, including images, and are given the opportunity to diagnose the patient. This is an excellent resource for students in the health sciences to familiarize themselves with using patient history and laboratory results to diagnose. It is also a helpful site for educators to use to introduce or test student learning in pulmonary pathology

Pathology Case Study: Progressive Shortness of Breath

This is a case study presented by the University of Pittsburgh Department of Pathology, which describes a 67-year-old man who presented to the emergency department with worsening dyspnea and cough for 8 months and new onset chest pain. Visitors are given patient history, immunohistochemistry, and both gross and microscopic descriptions, including images, and are also given the opportunity to diagnose the patient. A &quot;Final Diagnosis&quot; section provides a discussion of the findings as well as references. This is an excellent resource for students in the health sciences to familiarize themselves with using patient history and laboratory results to diagnose disease. It is also a helpful site for educators to use to introduce or test student learning in pulmonary pathology

Pathology Case Study: Retroperitoneal Masses

This site contains two case studies presented by the University of Pittsburgh Department of Pathology: one in which a man was experiencing increased pain in his left flank over the course of three weeks, and the second one in which a women experiencing persistent right lower quadrant pain shows a retroperitoneal lesion on CT scan. Visitors are given both the microscopic and gross descriptions, including images, and are given the opportunity to diagnose the patients. This is an excellent resource for students in the health sciences to familiarize themselves with using patient history and laboratory results to diagnose disease. It is also a helpful site for educators to use to introduce or test student learning in soft tissue pathology

Pathology Case Study: Mass in the Right Ischial Rectal Fossa

This is a case study presented by the University of Pittsburgh Department of Pathology in which a 30-year-old man presented with &quot;four-month history of worsening symptoms of urinary frequency, urgency and hesitancy and change in stool caliber.&quot; Visitors are given both the gross and microscopic descriptions, including images, and are given the opportunity to diagnose the patient. This is an excellent resource for students in the health sciences to familiarize themselves with using patient history and laboratory results to diagnose disease. It is also a helpful site for educators to use to introduce or test student learning in soft tissue pathology

Pathology Case Study: Pulmonary Mass

This is a case study presented by the University of Pittsburgh Department of Pathology, which describes &quot;a 46-year-old gentleman with a persistent right lower lobe pulmonary mass after a successfully treated cavitary pneumonia 5 months ago.&quot; Visitors are given patient history along with radiology findings and images. They are also given gross and microscopic descriptions, including images, and are given the opportunity to diagnose the patient. A &quot;Final Diagnosis&quot; section provides a discussion of the findings as well as references. This is an excellent resource for students in the health sciences to familiarize themselves with using patient history and laboratory results to diagnose disease. It is also a helpful site for educators to use to introduce or test student learning in pulmonary pathology

Clinical significance of CMV-specific T helper responses in lung transplant recipients

Background. Cytomegalovirus (CMV) disease continues to be a major problem for lung transplant patients who generate an inefficient immune response to control this viral infection. Both T helper and cytotoxic T cells are thought to play an important role in prevention and control of CMV disease. We investigated the clinical significance of CMV-specific memory responses in lung transplant recipients. Method. Peripheral blood samples (140) were collected from 99 lung transplant recipients. Patients were grouped according to their pre-transplant CMV serological status as recipient/donor (R−/D+, 25 patients), 28 R+/D+ patients, 35 R+/D− patients and 11 R−/D− patients. Memory responses to CMV whole antigen, 5 CMV proteins, and tetanus toxoid (TT) were measured in a 6-day proliferative assay. Results were expressed as the stimulation index (SI = experimental cpm/background cpm), and were considered positive if the SI was >3 and the cpm values were over 1,000. Results. The frequency of positive CMV memory responses was similar in three groups: 64% for R−/D+, 63% for R+/D+ and 56% for R+/D− except for R−/D− (21%). The memory response to TT was similar for all four groups (70% of samples were positive). The level of responsiveness to individual CMV proteins was much higher in R+/D+ group (65%) than the other two groups (35% for R+/D−, and 31% for R−/D+). We determined the temporal relationship between the presence of CMV-specific memory responses and the diagnosis of CMV disease. In the R−/D+ group, 16 of 17 patients who had CMV disease eventually developed CMV-specific memory. In those patients ( n = 3) who failed to develop CMV-specific T helper response for a prolonged time, all had recurrent CMV disease. In the R+/D+ group, 4 of 8 patients with CMV disease exhibited CMV-specific memory responses. Three of 4 patients in whom we observed a persistent absence of CMV-specific memory had multiple episodes of CMV pneumonitis. In the R+/D− group, only one of 4 patients with CMV disease had suppressed CMV-specific memory response after first episode of CMV pneumonitis and had recurrent disease. Conclusion. In lung transplant recipients, the loss or persistent lack of CMV-specific memory following infection was associated with chronic CMV disease. These data suggest that monitoring T helper memory responses following primary CMV infection or after augmented immunosuppression for treatment of rejection may identify those patients at risk for morbidity associated with recurrent CMV disease