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PubMed2007

Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an alpha-smooth muscle actin-Cre transgenic mouse.

BACKGROUND: Epithelial to mesenchymal transition (EMT) in alveolar epithelial cells (AECs) has been widely observed in patients suffering interstitial pulmonary fibrosis. In vitro studies have also demonstrated that AECs could convert into myofibroblasts following exposure to TGF-beta1. In this study, we examined whether EMT occurs in bleomycin (BLM) induced pulmonary fibrosis, and the involvement of bronchial epithelial cells (BECs) in the EMT. Using an alpha-smooth muscle actin-Cre transgenic mouse (alpha-SMA-Cre/R26R) strain, we labelled myofibroblasts in vivo. We also performed a phenotypic analysis of human BEC lines during TGF-beta1 stimulation in vitro. METHODS: We generated the alpha-SMA-Cre mouse strain by pronuclear microinjection with a Cre recombinase cDNA driven by the mouse alpha-smooth muscle actin (alpha-SMA) promoter. alpha-SMA-Cre mice were crossed with the Cre-dependent LacZ expressing strain R26R to produce the double transgenic strain alpha-SMA-Cre/R26R. beta-galactosidase (betagal) staining, alpha-SMA and smooth muscle myosin heavy chains immunostaining were carried out simultaneously to confirm the specificity of expression of the transgenic reporter within smooth muscle cells (SMCs) under physiological conditions. BLM-induced peribronchial fibrosis in alpha-SMA-Cre/R26R mice was examined by pulmonary betagal staining and alpha-SMA immunofluorescence staining. To confirm in vivo observations of BECs undergoing EMT, we stimulated human BEC line 16HBE with TGF-beta1 and examined the localization of the myofibroblast markers alpha-SMA and F-actin, and the epithelial marker E-cadherin by immunofluorescence. RESULTS: betagal staining in organs of healthy alpha-SMA-Cre/R26R mice corresponded with the distribution of SMCs, as confirmed by alpha-SMA and SM-MHC immunostaining. BLM-treated mice showed significantly enhanced betagal staining in subepithelial areas in bronchi, terminal bronchioles and walls of pulmonary vessels. Some AECs in certain peribronchial areas or even a small subset of BECs were also positively stained, as confirmed by alpha-SMA immunostaining. In vitro, addition of TGF-beta1 to 16HBE cells could also stimulate the expression of alpha-SMA and F-actin, while E-cadherin was decreased, consistent with an EMT. CONCLUSION: We observed airway EMT in BLM-induced peribronchial fibrosis mice. BECs, like AECs, have the capacity to undergo EMT and to contribute to mesenchymal expansion in pulmonary fibrosis.

Actins↗
PubMed2006

Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test.

RATIONALE AND HYPOTHESIS: Idiopathic pulmonary fibrosis is a fatal disease with a variable rate of progression. We hypothesized that changes in distance walked and quantity of desaturation during a six-minute-walk test (6MWT) would add prognostic information to changes in FVC or diffusing capacity for carbon monoxide. METHODS: One hundred ninety-seven patients with idiopathic pulmonary fibrosis were evaluated. Desaturation during the 6MWT was associated with increased mortality even if a threshold of 88% was not reached. Baseline walk distance predicted subsequent walk distance but was not a reliable predictor of subsequent mortality in multivariate survival models. The predictive ability of serial changes in physiology varied when patients were stratified by the presence/absence of desaturation < or = 88% during a baseline 6MWT. For patients with a baseline saturation < or = 88% during a 6MWT, the strongest observed predictor of mortality was serial change in diffusing capacity for carbon monoxide. For patients with saturation > 88% during their baseline walk test, serial decreases in FVC and increases in desaturation area significantly predicted subsequent mortality, whereas decreases in walk distance and in diffusing capacity for carbon monoxide displayed less consistent statistical evidence of increasing mortality in our patients. CONCLUSION: These data highlight the importance of stratifying patients by degree of desaturation during a 6MWT before attributing prognostic value to serial changes in other physiologic variables.

Aged↗
PubMed2002

Current status of gene therapy for cystic fibrosis pulmonary disease.

Cystic fibrosis (CF) is a common lethal genetic disorder that affects all ethnic populations; however, it is most prevalent in Caucasians. Intensive basic research over the last 20 years has resulted in a wealth of information regarding the CF gene, its protein product and the mutational basis of disease. This increased understanding has lead to the development of gene therapy for the treatment of CF pulmonary disease. Delivery of the CF gene to the airway requires direct in vivo transfer using vectors encoding for normal CF transmembrane regulator (CFTR) protein. Several vectors are currently available for CF gene transfer and include both viral (adenoviruses, adeno-associated viruses) and non-viral (liposomal) systems. Initial clinical trials with each of these vectors have demonstrated that gene transfer to the CF airway is possible. The efficiency of transfer and duration of expression, however, have been limited. The effects of gene transfer on correction of the basic ion transport defects have also been highly variable and inconsistent, irrespective of the vector. Currently, the risk of severe immunological reactions is the primary factor limiting the clinical advancement of gene therapy. Both the adenoviral and liposomal vectors are associated with significant acute inflammatory reactions. The adenoviruses and adeno-associated viruses also elicit humoral immune responses that significantly reduce the efficiency of transgene expression and increase the risk of readministration. Several strategies are under investigation to improve the efficiency of gene transfer to the CF airway. These include overcoming local barriers in the lung, circumventing the immune response and improving vector internalization and/or uptake. Application of gene transfer in the child and possibly the fetus are also potential future clinical applications of gene therapy. However, despite considerable research with gene therapy, there is little evidence to suggest that a well tolerated and effective gene transfer method is imminent and aggressive use of conventional pharmacological therapies currently offer the greatest promise in the treatment of patients with CF.

Cystic Fibrosis↗
PubMed1999

Expression of B7-1, B7-2, and interleukin-12 in anti-Fas antibody-induced pulmonary fibrosis in mice.

BACKGROUND: We have previously reported that the inhalation of anti-Fas antibody induced pulmonary fibrosis in mice. To induce an effective immune response, antigen-presenting cells have to not only present antigenic peptide with MHC molecules to T lymphocytes, but also express B7 costimulating molecules. The purpose of this study is to investigate whether B7 family costimulating molecules and interleukin-12 (IL-12), which primarily promote cellular immunity, are associated with anti-Fas antibody-induced pulmonary fibrosis. METHODS: We examined the expression of B7-1, B7-2, and IL-12 using the revese transcription-polymerase chain reaction (RT-PCR), RT-in situ PCR, and immunohistochemistry. RESULTS: We observed the upregulation of B7-1, B7-2, and IL-12 p40 mRNA after anti-Fas antibody inhalation. B7-2 and IL-12 p40 mRNA appeared to be expressed in mononuclear cells, while B7-1 mRNA and protein were expressed in bronchiolar epithelial cells as well as macrophages. CONCLUSION: These findings indicate that the T-cell-mediated immune response in this model involved the upregulation of B7-1, B7-2, and IL-12, and that the aberrant expression of B7-1 in bronchiolar epithelial cells may induce autoreactive T cell proliferation against themselves.

Administration, Inhalation↗
PubMed1992

Prolonged monocyte accumulation in the lung during bleomycin-induced pulmonary fibrosis. A noninvasive assessment of monocyte kinetics by scintigraphy.

It has become more evident that monocytes, macrophages, and their products interact in a complex manner with various cell types in the lung, and may under the proper set of conditions contribute to the pathogenesis of pulmonary fibrosis. Current methods used to assess the lung content of mononuclear cells, which include tissue immunohistochemistry and bronchoalveolar lavage fluid analysis, sample the lung at one point in time and therefore provide only a "snapshot" of dynamic process. We utilized external imaging (scintigraphy) to provide a dynamic assessment of the trafficking patterns of radiolabeled monocytes in the lungs of rabbits in conjunction with lung tissue morphometry and bronchoalveolar lavage fluid analysis to determine the kinetics of neutrophil and monocyte accumulation in the alveolar walls and alveolar spaces of the lung during bleomycin-induced pulmonary fibrosis. We found that scintigraphy accurately reflected the accumulation of monocyte-associated radioactivity in the alveolar walls over time as well as the subsequent migration of these cells into alveolar spaces during the acute phase of bleomycin-induced lung injury (days 0 to 14) when compared with lung tissue morphometry. The scintigraphy, lavage, and morphometry data together showed that neutrophil influx into both of these lung compartments preceded that of monocytes by days, and that the influx of monocytes accounted for a major proportion of mononuclear cells found in the alveolar walls and alveolar spaces of the lung during this acute phase of inflammation. The increased numbers of neutrophils and mononuclear cells in alveolar spaces normalized by days 14 and 28 respectively, but in contrast to the normalization of neutrophil content in alveolar walls by day 10, increased numbers of mononuclear cells persisted in alveolar walls for up to 56 days, a time when there was a significant increase in the hydroxyproline content of these lungs. These data also show that the increased number of mononuclear cells present in the alveolar walls on days 28 and 56 was not due to a persistent influx of blood monocytes. These data suggest: (a) that differential pathways of efflux existed for alveolar wall versus alveolar space mononuclear cells, (b) that a delay in efflux from the alveolar walls occurred and/or that an increase in the local proliferation of mononuclear cells in this compartment may have been occurring during the later phases of bleomycin-induced lung injury, and (c) that this prolonged residence of mononuclear cells in the alveolar walls occurred concurrently with the development of pulmonary fibrosis.

Animals↗
PubMed2004

Therapeutic targeting of IL-4- and IL-13-responsive cells in pulmonary fibrosis.

Severe forms of idiopathic interstitial pneumonia (IIP), such as usual interstitial pneumonia (UIP), can be impervious to modern steroid and immunosuppressive treatment regimens, thereby emphasizing the need for novel effective therapies. Understanding the cytokine networks that may affect immune and structural cell activation and, hence, the progression of these fatal fibrotic diseases, has been a focus in our research. In this regard, we have examined the role of interleukin (IL)-4 and IL-13 and their respective receptor subunits in this process. Examination of clinical surgical lung biopsies (SLBs) showed that IIP is characterized by the abnormal, heightened expression of the receptor subunits that bind IL-4 and IL-13. Specifically, IL-4Ralpha and IL-13Ralpha2 (the high-affinity IL-13 receptor subunit) was present in greater abundance in SLBs and fibroblasts from IIP patients compared with normal patients, who exhibited no evidence of pulmonary fibrosis. These clinical findings prompted us to investigate whether the targeting of pulmonary cell types that were highly responsive to IL-4 and IL-13 was a viable therapeutic option in IIP. Using a chimeric protein comprised of human IL-13 and a truncated version of an exotoxin from Pseudomonas (abbreviated IL13-PE), we observed that IL13-PE selectively targeted human pulmonary fibroblasts grown from IIP SLBs, whereas it had a minimal effect on fibroblasts grown from biopsies from normal patients. In murine models characterized by abnormal airway or interstitial fibrotic responses, the intranasal administration of IL13-PE significantly attenuated the fibrotic response through the targeting of IL-4Ralpha- and IL-13Ralpha2-expressing pulmonary cells, including monocytes, macrophages, and pulmonary fibroblasts. Together, these data demonstrate that IL-4 and IL-13 are required for the initiation and maintenance of pulmonary fibrosis, and highlight the importance of further investigation of anti-fibrotic therapeutics that prevent the action of both cytokines during clinical pulmonary fibrosis.

Animals↗
PubMed2001

Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis.

The caspase cascade is an executioner of apoptosis, mediated by Fas. Fas-associating protein with death domain (FADD) interacts with Fas and initiates apoptosis through activating caspase-8. It has previously been demonstrated that the Fas-Fas ligand pathway may be involved in the pathophysiology of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate Fas-signalling molecules in epithelial cells in IPF. The immunohistochemistry for FADD and caspase-1 and -3 and terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick endlabelling (TUNEL) methods were performed in lung tissues from 10 patients with IPF obtained by thoracoscopic biopsy and in seven normal lung parenchyma specimens. The induction of caspases expression and activation by Fas-ligation on lung epithelial cell line A549 was also investigated. The immunoreactivity grade for FADD and caspase-1 and -3, and positive signals for TUNEL were significantly increased in epithelial cells of IPF compared with controls. Fas-ligation induced upregulation of caspase-1 and -3 expression in the nucleus and cytoplasm in A549 cells. Procaspase-1, -3, and -8 were activated in apoptotic cells, but not in viable cells. Although direct measurement of the caspase activity in lung epithelial cells of idiopathic pulmonary fibrosis could not be made, these results suggest that the Fas-signalling pathway is upregulated in lung epithelial cells of idiopathic pulmonary fibrosis.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Efficacy of cyclosporine to reduce steroids in patients with idiopathic pulmonary fibrosis before lung transplantation.

Lung transplantation today is considered an effective option for patients with severe idiopathic pulmonary fibrosis. The standard medical treatment for this disease consists of high-dose steroids alone or combined with other immunosuppressive drugs. Unfortunately, pretransplantation administration of steroids may jeopardize the healing of the airway anastomosis and cause other complications; therefore it is considered a relative contraindication to lung transplantation. For this reason we try to reduce the dose of prednisone to 15 to 20 mg/day or less before the transplantation, but this creates many difficulties and is sometimes impossible in severely ill patients. Therefore we used cyclosporine (4 to 7 mg/kg/day) in 10 patients who were receiving high-dose prednisone (> or = 50 mg/day) therapy, but who were otherwise suitable candidates for lung transplantation. In seven cases prednisone could be tapered to 20 mg/day or less, allowing acceptance in our program. These patients had a CRP score of 60 or more before entering our trial and remained stable at this level after conversion to cyclosporine. The 6-minute walk test showed a mild improvement in five cases (71.5%). Three patients underwent single lung transplantation; two patients are on our waiting list after 3.5 and 4 months of treatment with cyclosporine and prednisone (10 mg/day), and two patients died while awaiting a suitable organ 6 and 7.5 months after starting cyclosporine therapy. Combined administration of cyclosporine and prednisone may extend the waiting time while receiving low-dose steroids and allow more patients with idiopathic pulmonary fibrosis to qualify for lung transplantation while reducing the risk of steroid-induced complications.

Adult↗
PubMed2002

Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition.

Treatment options for patients with pulmonary fibrosis associated with rheumatoid disease are limited. We report a case of a 71-year-old man with a 3-year history of seropositive rheumatoid arthritis (RA) referred to the pulmonary clinic because of progressive pulmonary symptoms associated with radiographic fibrosis that was progressive in spite of corticosteroid treatment. In an attempt to control his articular symptoms and alter the course of his pulmonary fibrosis, treatment with IV infusion of the tumor necrosis factor (TNF)-alpha inhibitor infliximab was initiated. Following 1 year of therapy with this agent, the patient reported sustained improvement in dyspnea, cough, and exercise tolerance, in addition to improvement in joint symptoms. Stabilization of pulmonary function was indicated by repeat pulmonary function test findings. This report suggests that inhibition of TNF-alpha may be of significant benefit to patients with fibrosing lung conditions in the setting of RA.

Aged↗
PubMed1995

HLA association with sarcoidosis and diffuse interstitial pulmonary fibrosis.

HLA typing was performed on 18 patients suffering from sarcoidosis and 30 patients suffering from diffuse interstitial pulmonary fibrosis. One hundred normal healthy people ethnically matched served as the controls. On statistical analysis, the corrected 'p' value of all the HLA antigens for both the patient groups was non significant. The results therefore suggest that there is no particular HLA antigen associated with sarcoidosis and diffuse interstitial pulmonary fibrosis.

Case-Control Studies↗
PubMed2005

Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice.

Imatinib mesylate is a potent and specific tyrosine kinase inhibitor against c-ABL, BCR-ABL, and c-KIT, and has been demonstrated to be highly active in chronic myeloid leukemia and gastrointestinal stromal tumors. We examined the antifibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFRs). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-beta induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis in mice, partly by reducing the number of mesenchymal cells incorporating bromodeoxyuridine. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on Days 7 and 14 caused by bleomycin. These results suggest that imatinib has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.

Animals↗
PubMed2005

Keratinocyte growth factor expression by fibroblasts in pulmonary fibrosis: poor response to interleukin-1beta.

Keratinocyte growth factor (KGF) is secreted by fibroblasts and protects from pulmonary fibrosis in animal models. Interleukin (IL)-1beta is the most potent inducer of KGF in fibroblasts, acting through the c-Jun pathway. We evaluated in vitro KGF production by human lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF, n = 10) and from control subjects (n = 7) at baseline and after IL-1beta stimulation. Basal KGF secretion by IPF fibroblasts was similar to controls. In fibroblasts from control subjects, IL-1beta increased c-Jun expression, c-Jun activation, and KGF secretion. SP600125, a specific c-Jun N-terminal kinase (JNK) inhibitor, inhibited the effect of IL-1beta. By contrast, in IPF fibroblasts, IL-1beta did not increase c-Jun expression and c-Jun activation, and weakly increased KGF secretion, whereas SP600125 had no effect. IL-1beta similarly increased JunB expression in fibroblasts from patients with IPF and control subjects. Total JNK content was not different in either unstimulated or IL-1beta-stimulated IPF and control fibroblasts. IL-1beta increased phosphorylated JNK in control and IPF fibroblasts, but this increase was weaker and heterogeneous in IPF. Altogether, our results demonstrate a dysregulation of KGF secretion by IPF fibroblasts. The weak response to IL-1beta is associated with a defect of c-Jun expression and activation and a defect of JNK activation.

Adult↗
PubMed1999

[Idiopathic pulmonary fibrosis in a 14-year-old girl].

Pulmonary fibrosis (PF) is a rare disease that develops as the final stage of scarring after a series of episodes of lung injury. PF is idiopathic in most cases (60%), though the exact rate varies from series to series. Childhood PF, which is even rarer than the adult form, is usually diagnosed when the patient is less than five years old. Some cases are familial. We report the case of a 14-year-old girl admitted with a three-year history of dry cough and increasing dyspnea that eventually appeared even with moderate effort. Pulmonary biopsy by mini-thoracotomy showed diffuse fibrosis of unknown cause. She died four years after diagnosis. The patient's age, the rapid course of disease, and the final outcome are all unusual features of this case.

Adolescent↗
PubMed2005

[An experiment study of protection and treatment of Kudan granule on rats of pulmonary fibrosis induced by pinyangmycin].

OBJECTIVE: To explore the protection and treatment effects of Kudan granule on rats of pulmonary fibrosis induced by pinyangmycin. METHOD: In asepsis condition, rat was anaesthetized by 3.5% chloral hydrate, inserted the needle above the bifurcation of trachea and injecting 5 mg x kg(-1) pinyangmycin normal saline solution. RESULT: For model-group rats, after injecting pinyangmycin at 7, 14, 28, 56 days, there were mass inflammation cell infiltration at pulmonary alveoli and interstitial, the pulmonary alveolar wall and interstitial thickened obviously, and the pulmonary interval broadened distinctly. The structure of collagen fiber was destroyed, and the pulmonary alveoli disappeared. By Masson dyeing, there were hunk collagen fiber and the consolidation of lung had come into being. Compared with the model group, the rats of Kudan granule big-dose group, at 7, 14, 28, 56 days after injecting pinyangmycin, there were still much inflammation cell infiltration at pulmonary alveoli and interstitial, pulmonary interstitial edema and spotty necrosis, thickened alveolar wall, broadened pulmonary interval, and much collagen fiber in pulmonary interstitial, but there was not bunk the consolidation of lung. The curative effect of Kudan granule small-dose group was not better than that of Kudan granule big-dose group, because there were still bunk collagen fiber and the consolidation of lung in pulmonary interstitial. Although the destroyed area was more than 50%, it was better than that of the model-group. CONCLUSION: The big-dose Kudan granule show the better function of protection and treatment for pulmonary fibrosis of rats induced by pinyangmycin.

Animals↗
PubMed1992

[Experimental study of the effect of IH764-3, a potent component isolated from salviae milltiorrhize, against pulmonary fibrosis].

IH764-3, an effective component isolated from Salvae milliorrhize (a component of traditional Chinese medicine) was used against pulmonary fibrosis in this study. The results indicated that in the treated group, lung coefficient, surfactant, hydroxyproline content and FGF activity were significantly lower than those in the model group. Electron microscopic observation confirmed that the pulmonary ultrastructure was improved remarkably in the treated group: the proliferation of collagen-forming cells and infiltration of inflammatory cells, collagen and elastic fibers were obviously less. All the results demonstrated that IH764-3 has prophylactic and therapeutic effects on the development of pneumonitis and pulmonary fibrosis.

Animals↗