William D. Cornwell

Pathogenesis of inflammation and repair in advanced COPD.

Chronic obstructive pulmonary disease is characterized by an abnormal persistent inflammatory response to noxious environmental stimuli, most commonly cigarette smoke. Although cigarette smoking elicits airway inflammation in all of those who smoke, persistent inflammation and clinically significant COPD occurs in only a minority of smokers. The pathogenesis of COPD involves the recruitment and regulation of neutrophils, macrophages, and lymphocytes to the lung, as well as the induction of oxidative stress, all of which result in lung parenchymal destruction and airway remodeling. Recent research has generated a greater understanding of the mechanisms responsible for COPD development, including new concepts in T cell biology and the increasing recognition that the processes governing lung cell apoptosis are upregulated. We are also starting to understand the reasons for continued inflammation even after smoking cessation, which accelerates the rate of lung function decline in COPD. Herein we review our current knowledge of the inflammatory pathways involved in COPD pathogenesis, as well as newer concepts that have begun to unfold in recent years.

Attenuation of Experimental Atherosclerosis by Interleukin-19

Objective—Interleukin-19 (IL-19) is a putative Th2, anti-inflammatory interleukin. Its expression and potential role in atherogenesis are unknown. IL-19 is not detected in normal artery and is expressed to a greater degree in plaque from symptomatic versus asymptomatic patients, suggesting a compensatory counter-regulatory function. We tested whether IL-19 could reduce atherosclerosis in susceptible mice and identified plausible mechanisms. Approach and Results—LDLR−/− mice fed an atherogenic diet and injected with either 1.0 or 10.0 ng/g per day recombinant mouse IL-19 had significantly less plaque area in the aortic arch compared with controls (P<0.0001). Weight gain, cholesterol, and triglyceride levels were not significantly different. Gene expression in splenocytes from IL-19–treated mice demonstrated immune cell Th2 polarization, with decreased expression of T-bet, interferon-&ggr;, interleukin-1&bgr;, and interleukin-12&bgr; and increased expression of GATA3 and FoxP3 mRNA. A greater percentage of lymphocytes were Th2 polarized in IL-19–treated mice. Cellular characterization of plaque by immunohistochemistry demonstrated that IL-19–treated mice have significantly less macrophage infiltrate compared with controls (P<0.001). Intravital microscopy revealed significantly less leukocyte adhesion in wild-type mice injected with IL-19 and fed an atherogenic diet compared with controls. Treatment of cultured endothelial cells, vascular smooth muscle cells, and bone marrow–derived macrophages with IL-19 resulted in a significant decrease in chemokine mRNA and mRNA stability protein human antigen R. Conclusions—These data suggest that IL-19 is a potent inhibitor of experimental atherosclerosis, with diverse mechanisms including immune cell polarization, decrease in macrophage adhesion, and decrease in gene expression. This may identify IL-19 as a novel therapeutic to limit vascular inflammation.

Chronic Bronchitis and Current Smoking Are Associated with More Goblet Cells in Moderate to Severe COPD and Smokers without Airflow Obstruction

Background Goblet cell hyperplasia is a classic but variable pathologic finding in COPD. Current literature shows that smoking is a risk factor for chronic bronchitis but the relationship of these clinical features to the presence and magnitude of large airway goblet cell hyperplasia has not been well described. We hypothesized that current smokers and chronic bronchitics would have more goblet cells than nonsmokers or those without chronic bronchitis (CB), independent of airflow obstruction. Methods We recruited 15 subjects with moderate to severe COPD, 12 healthy smokers, and 11 healthy nonsmokers. Six endobronchial mucosal biopsies per subject were obtained by bronchoscopy and stained with periodic acid Schiff-Alcian Blue. Goblet cell density (GCD) was quantified as goblet cell number per millimeter of basement membrane. Mucin volume density (MVD) was quantified as volume of mucin per unit area of basement membrane. Results Healthy smokers had a greater GCD and MVD than nonsmokers and COPD subjects. COPD subjects had a greater GCD than nonsmokers. When current smokers (healthy smokers and COPD current smokers, n = 19) were compared with all nonsmokers (nonsmoking controls and COPD ex-smokers, n = 19), current smokers had a greater GCD and MVD. When those with CB (n = 12) were compared to those without CB (n = 26), the CB group had greater GCD. This finding was also seen in those with CB in the COPD group alone. In multivariate analysis, current smoking and CB were significant predictors of GCD using demographics, lung function, and smoking pack years as covariates. All other covariates were not significant predictors of GCD or MVD. Conclusions Current smoking is associated with a more goblet cell hyperplasia and number, and CB is associated with more goblet cells, independent of the presence of airflow obstruction. This provides clinical and pathologic correlation for smokers with and without COPD.

Effect of chronic morphine administration on circulating T cell population dynamics in rhesus macaques

Opioid receptor agonists modulate both innate and adaptive immune responses. In this study, we examined the impact of long-term chronic morphine administration on the circulating T cell population dynamics in rhesus macaques. We found that the numbers of circulating Treg cells, and the functional activity of Th17 cells, were significantly increased with chronic morphine exposure. Our results also show that T cell populations with surface markers characteristic of gut-homing (CD161 and CCR6) and HIV-1 susceptibility (CCR5 and β7 integrin) were increased. These results represent the first detailed report of the impact of chronic morphine administration on circulating T cell dynamics.

Transcriptional regulation of the major HIV‐1 coreceptor, CXCR4, by the κ opioid receptor

Previous studies have demonstrated that KOR activation results in decreased susceptibility to infection by HIV‐1 in human PBMCs. In the present studies, we have found this effect is, in part, a result of down‐regulation of the major HIV‐1 coreceptor, CXCR4. Using a combination of biochemical approaches, our results show that CXCR4 protein and mRNA levels were reduced significantly following KOR activation. We evaluated the nature of the signaling pathway(s), which were induced by KOR activation, using transcription factor‐binding array analysis and comparing extracts from control and KOR‐activated cells. We determined that the IRFs and STATs were induced following KOR activation, and these events were important for the inhibition of CXCR4 expression. Using chemical inhibitors and siRNA constructs, we determined that JAK2, STAT3, and IRF2 were critical members of this signal transduction pathway. Immediately following KOR activation, JAK2 was phosphorylated, and this was required for the phosphorylation/activation of STAT3. Moreover, IRF2 mRNA and protein expression were also up‐regulated, and further studies using ChIP analysis showed that IRF2 was induced to bind in vivo to the CXCR4 promoter. This is the first report detailing the initiation of a KOR‐induced JAK2/STAT3 and IRF2 signaling cascade, and these pathways result in substantial down‐regulation of CXCR4 expression. The capacity of KOR to down‐regulate CXCR4 expression may provide a strategy for the development of novel therapeutics for the inhibition of HIV replication.

Cross-Desensitization of CCR1, but Not CCR2, following Activation of the Formyl Peptide Receptor FPR1

The cross-regulation of G protein–coupled receptors (GPCRs) plays an important role in the immune response. Studies from several laboratories have suggested that a hierarchy of sensitivities to cross-desensitization exists for the chemoattractant GPCRs. We carried out experiments to study the capacity of the formyl peptide receptor-1 (FPR1) to desensitize chemokine receptors CCR1 and CCR2. Our results show that activation of FPR1 resulted in the desensitization and partial internalization of CCR1, but not CCR2, in both primary human monocytes and HEK293 cells coexpressing CCR1, CCR2, and FPR1 (HR1R2F cells). The desensitization of CCR1 by FPR1 stimulation was not due to the simple depletion of the Ca2+ stores, but was dependent on activation of protein kinase C. Furthermore, we found that the cross-desensitization of CCR1 by FPR1 was associated with CCR1 phosphorylation and moderate reduction of CCR1 cell-surface expression. In contrast, CCR2 was not phosphorylated or internalized after FPR1 activation. Additional studies showed that optimal cross talk between FPR1 and CCR1 was dependent on the functional activity of protein kinase Cβ. These results provide a mechanistic basis for the capacity of certain GPCR ligands to exert rapid and selective cross-inactivation of other chemoattractant receptors, and suggest that FPR1 is able to exert “traffic control” in the migration of inflammatory cells by rapidly inhibiting the cell responses to potentially “low-priority” chemoattractants such as CCR1 agonists without inhibiting the response to “higher priority” CCR2 chemoattractants.

Activation and polarization of circulating monocytes in severe chronic obstructive pulmonary disease

BackgroundThe ability of circulating monocytes to develop into lung macrophages and promote lung tissue damage depends upon their phenotypic pattern of differentiation and activation. Whether this phenotypic pattern varies with COPD severity is unknown. Here we characterize the activation and differentiation status of circulating monocytes in patients with moderate vs. severe COPD.MethodsBlood monocytes were isolated from normal non-smokers (14), current smokers (13), patients with moderate (9), and severe COPD (11). These cells were subjected to analysis by flow cytometry to characterize the expression of activation markers, chemoattractant receptors, and surface markers characteristic of either M1- or M2-type macrophages.ResultsPatients with severe COPD had increased numbers of total circulating monocytes and non-classical patrolling monocytes, compared to normal subjects and patients with moderate COPD. In addition, while the percentage of circulating monocytes that expressed an M2-like phenotype was reduced in patients with either moderate or severe disease, the levels of expression of M2 markers on this subpopulation of monocytes in severe COPD was significantly elevated. This was particularly evident for the expression of the chemoattractant receptor CCR5.ConclusionsBlood monocytes in severe COPD patients undergo unexpected pre-differentiation that is largely characteristic of M2-macrophage polarization, leading to the emergence of an unusual M2-like monocyte population with very high levels of CCR5. These results show that circulating monocytes in patients with severe COPD possess a cellular phenotype which may permit greater mobilization to the lung, with a pre-existing bias toward a potentially destructive inflammatory phenotype.

Effect of chronic morphine administration on circulating dendritic cells in SIV-infected rhesus macaques

We studied the effect of chronic morphine administration on the circulating dendritic cell population dynamics associated with SIV infection using rhesus macaques. Animals were either first infected with SIV and then given chronic morphine, or visa versa. SIV infection increased the numbers of myeloid DCs (mDCs), but morphine treatment attenuated this mDC expansion. In contrast, morphine increased the numbers of plasmacytoid DCs (pDCs) in SIV-infected animals. Finally, chronic morphine administration (no SIV) transiently increased the numbers of circulating pDCs. These results show that chronic morphine induces a significant alteration in the available circulating levels of critical antigen-presenting cells.

Smoking and lung inflammation

Smoking and lung inflammation : , Smoking and lung inflammation : , کتابخانه دیجیتال جندی شاپور اهواز

Monocyte Populations Which Participate in Chronic Lung Inflammation

Monocytes are a member of the family of mononuclear phagocytes, which are composed of monocytes, macrophages, and dendritic cells. These cells play a crucial role in the innate immune response but are also essential for adaptive immunity. Very importantly, these cells also exert a major influence on both acute and chronic inflammatory reactions. Each of the members of this family is made up of multiple subtypes, and our understanding of the regulation of their function is still not fully developed. In this chapter we will review current knowledge regarding the function of monocytes and macrophages, and in particular we will examine the role of these cells in chronic inflammatory responses in organ systems such as the lung.