transforming-growth-factor-beta and Pleurisy

Pleural fibrosis resembles fibrosis in other tissues and can be defined as an excessive deposition of matrix components that results in the destruction of normal pleural tissue architecture and compromised function. Pleural fibrosis may be the consequence of an organised haemorrhagic effusion, tuberculous effusion, empyema or asbestos-related pleurisy and can manifest itself as discrete localised lesions (pleural plaques) or diffuse pleural thickening and fibrosis. Although the pathogenesis is unknown, it is likely that the complex interactions between resident and inflammatory cells, profibrotic mediators and coagulation, and fibrinolytic pathways are integral to pleural remodelling and fibrosis. It is generally considered that the primary target cell for pleural fibrosis is the subpleural fibroblast. However, increasing evidence suggests that mesothelial cells may also play a significant role in the pathogenesis of this condition, both by initiating inflammatory responses and producing matrix components. A greater understanding of the interactions between pleural and inflammatory cells, cytokines and growth factors, and blood derived proteins is required before adequate therapies can be developed to prevent pleural fibrosis from occurring.

Topics: Asbestosis; Epithelium; Fibrinolysis; Fibrosis; Humans; Platelet-Derived Growth Factor; Pleura; Pleural Diseases; Pleurisy; Thromboplastin; Transforming Growth Factor beta

Mesothelial to mesenchymal transition (MesoMT) is one of the crucial mechanisms underlying pleural fibrosis, which results in restrictive lung disease. DOCK2 (dedicator of cytokinesis 2) plays important roles in immune functions; however, its role in pleural fibrosis, particularly MesoMT, remains unknown. We found that amounts of DOCK2 and the MesoMT marker α-SMA (α-smooth muscle actin) were significantly elevated and colocalized in the thickened pleura of patients with nonspecific pleuritis, suggesting the involvement of DOCK2 in the pathogenesis of MesoMT and pleural fibrosis. Likewise, data from three different pleural fibrosis models (TGF-β [transforming growth factor-β], carbon black/bleomycin, and streptococcal empyema) consistently demonstrated DOCK2 upregulation and its colocalization with α-SMA in the pleura. In addition, induced DOCK2 colocalized with the mesothelial marker calretinin, implicating DOCK2 in the regulation of MesoMT. Our

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Disease Models, Animal; Epithelial-Mesenchymal Transition; Epithelium; Fibrosis; GTPase-Activating Proteins; Guanine Nucleotide Exchange Factors; Humans; Mice; Mice, Inbred C57BL; Pleura; Pleurisy; Signal Transduction; Transforming Growth Factor beta

The mechanisms of the systemic response associated with talc-induced pleurodesis are poorly understood. The aim of this study was to assess the acute inflammatory response and migration of talc of small size particles injected in the pleural space. Rabbits were injected intrapleurally with talc solution containing small or mixed particles and blood and pleural fluid samples were collected after 6, 24 or 48 h and assayed for leukocytes, neutrophils, lactate dehydrogenase, IL-8, VEGF, and TGF-beta. The lungs, spleen, liver and kidneys were assessed to study deposit of talc particles. Both types of talc produced an acute serum inflammatory response, more pronounced in the small particles group. Pleural fluid IL-8 and VEGF levels were higher in the small particle talc group. Correlation between pleural VEFG and TGF-beta levels was observed for both groups. Although talc particles were demonstrated in the organs of both groups, they were more pronounced in the small talc group. In conclusion, intrapleural injection of talc of small size particles produced a more pronounced acute systemic response and a greater deposition in organs than talc of mixed particles.

Topics: Acute-Phase Reaction; Animals; Biomarkers; Injections; Interleukin-8; Kidney; L-Lactate Dehydrogenase; Leukocyte Count; Leukocytes; Liver; Lung; Neutrophils; Particle Size; Pleural Effusion; Pleurisy; Pleurodesis; Rabbits; Spleen; Talc; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

In this study, we compared several immune parameters in tuberculosis (TB) and nontuberculosis (NTB) pleurisy to gain an understanding of the mechanism behind enhanced Th1 apoptosis that occurs at sites of active Myobacterium tuberculosis (M. tuberculosis) infection. An initial evaluation of the accumulated cytokines in pleural fluid (PF) demonstrated that both TB and NTB pleurisy were associated with prointflammatory cytokines, while only TB pleurisy had augmented expression of interferon (IFN)-gamma and soluble Fas ligand (sFASL). Despite enhanced expression of the apoptosis-inducing molecule in TB pleurisy, T cells derived from both types of pleurisy exhibited significant apoptosis. In both groups, T-cell apoptosis correlated with low expression of CD80 on PF-derived macrophages and elevated accumulation of TGF-beta in the PF. A causative correlation between TGF-beta and low CD80 expression in the two groups was established by in vitro studies demonstrating TGF-beta inhibition of CD80 upregulation in a macrophage cell line. Together, the findings allude to the possibility that activation in the absence of appropriate CD80 costimulation is the mechanism that leads to T-cell apoptosis at sites of active M. tuberculosis infection. Furthermore, the findings also indicate that T-cell apoptosis is perhaps a host regulatory mechanism to limit inflammation, rather than a pathogen-induced immune deviation.

Topics: Adult; Aged; Apoptosis; B7-1 Antigen; B7-2 Antigen; Cytokines; Female; Humans; Lipopolysaccharide Receptors; Male; Middle Aged; Pleurisy; T-Lymphocytes; Transforming Growth Factor beta; Tuberculosis, Pleural

Granulocyte apoptosis and subsequent clearance by phagocytes are critical for the resolution of inflammation. However, no studies have addressed how the resolution proceeds in the inflammatory site. We studied the time course of neutrophil apoptosis and the following ingestion by mononuclear leukocytes in rat carrageenin-induced pleurisy, detecting DNA fragmentation by the deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) method, by acridine orange staining, and from the DNA ladder pattern on electrophoresis. Neutrophil accumulation started 3-5 h after carrageenin injection and then maintained a plateau until 24 h. Neutrophils decreased steeply between days 1 and 3. Mononuclear leukocytes started to accumulate at 5 h and reached a peak at day 2. TUNEL-positive bodies and acridine orange-positive bodies first became detectable in the cytoplasm of the mononuclear leukocytes from 24 h and 9 h, respectively. Both methods indicated that mononuclear leukocytes containing fragmented DNA increased rapidly on days 1 and 2 and reached a peak at day 3. The characteristic ladder pattern of neutrophil DNA was observed from 5 h. Tumor necrosis factor alpha was detectable on the start, and the levels of interleukin-10 and transforming growth factor-beta1 rose together with signs of neutrophil apoptosis and the following ingestion by mononuclear leukocytes. These results indicate that neutrophils start to undergo apoptosis just after the beginning of their accumulation in the inflammation site. Thus, evolution and resolution processes may proceed concurrently in acute inflammation.

Topics: Acridine Orange; Animals; Apoptosis; Carrageenan; DNA; In Situ Nick-End Labeling; Interleukin-10; Leukocytes, Mononuclear; Male; Neutrophils; Phagocytosis; Pleurisy; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Although much attention has focused on pro-inflammatory pathways that initiate inflammation, relatively little is known about the mechanisms that switch off inflammation and resolve the inflammatory response. The transcription factor NF-kappaB is thought to have a central role in the induction of pro-inflammatory gene expression and has attracted interest as a new target for the treatment of inflammatory disease. We show here that NF-kappaB activation in leukocytes recruited during the onset of inflammation is associated with pro-inflammatory gene expression, whereas such activation during the resolution of inflammation is associated with the expression of anti-inflammatory genes and the induction of apoptosis. Inhibition of NF-kappaB during the resolution of inflammation protracts the inflammatory response and prevents apoptosis. This suggests that NF-kappaB has an anti-inflammatory role in vivo involving the regulation of inflammatory resolution.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-2-Associated X Protein; Carrageenan; Cysteine Endopeptidases; Female; Granuloma; Inflammation; Leukocytes; Leupeptins; Male; Mice; Multienzyme Complexes; NF-kappa B; Nitriles; Pleurisy; Proteasome Endopeptidase Complex; Protein Binding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrrolidines; Rats; Sulfones; Thiocarbamates; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Suppressor Protein p53