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PubMed1999

Interleukin-4-producing cells in idiopathic pulmonary fibrosis: an immunohistochemical study.

OBJECTIVE: Interleukin-4 stimulates collagen synthesis in fibroblasts in vitro. The purpose of this study was to clarify the role of interleukin-4 in the pathogenesis of idiopathic pulmonary fibrosis. METHODOLOGY: We compared interleukin-4 expressing cells in tissues from 11 patients with pathologically confirmed idiopathic pulmonary fibrosis with early stage inflammatory lesions versus advanced lesions. We also performed double staining in order to elucidate which inflammatory cells produce interleukin-4 in idiopathic pulmonary fibrosis. RESULTS: Greater numbers of interleukin-4 positive cells were observed in the advanced lesions than in the early lesions. We also found that early stage lesions showed a predominance of CD3/interleukin-4 double positive cells whereas, the advanced stage lesions had higher percentages of the EG2/interleukin-4 double positive cells and the tryptase/interleukin-4 double positive cells. CONCLUSIONS: Our results suggest that interleukin-4 may be involved in progression of interstitial fibrosis in idiopathic pulmonary fibrosis, in which we confirmed a significant contribution of eosinophils and mast cells to interleukin-4 production.

Adult↗
PubMed2002

[Losartan in the rat model of bleomycin-induced pulmonary fibrosis and its impact on the expression of monocyte chemoattractant protein-1 and basic fibroblast growth factor].

OBJECTIVE: To study the effect of losartan on bleomycin-induced pulmonary fibrosis in rats and its possible mechanism. METHODS: Pulmonary fibrosis was induced in Wistar rats by intratracheal instillation of bleomycin. Then the rats received daily losartan 10 mg/kg (group L), prednisone 20 mg/kg (group P), or normal saline (group B) orally. Normal controls received normal saline both intratracheally and orally. Six rats in each group were sacrificed 3, 7, 14, 28 and 56 days after intratracheal instillation. Histological changes of the lungs were evaluated by HE stain, Masson's trichrome stain and sirius red stain. Collagen content of the lung tissue was assessed by hydroxyproline concentration. The mRNAs of monocyte chemoattractant protein-1 (MCP-1) and basic fibroblast growth factor (bFGF) were detected by reverse transcription-polymerase chain reaction (RT-PCR). Lung expression of MCP-1 and bFGF proteins was assessed by immunohistochemistry and the level of MCP-1 protein was further measured by ELISA. RESULTS: Pulmonary fibrosis of group L and group P was improved as compared with that of group B. Hydroxyproline concentrations of group L and group P were lower than that of group B. Protein expression of MCP-1 and bFGF in group L was lower than that in group B. CONCLUSION: Losartan alleviates bleomycin-induced pulmonary fibrosis in rats. Inhibiting the expressions of MCP-1 and bFGF in lung tissues may be one of the mechanisms.

Administration, Oral↗
PubMed2001

FTS reduces bleomycin-induced cytokine and chemokine production and inhibits pulmonary fibrosis in mice.

Bleomycin (BLM), an antitumour drug, is known to cause interstitial pneumonia followed by pulmonary fibrosis, and has often been used to produce an animal model of pulmonary fibrosis. In the present study, we examined the effect of a nonapeptide thymic hormone, facteur thymique serique (FTS), on the murine lung fibrosis induced by intratracheal instillation of BLM. Treatment with FTS ameliorated BLM-induced fibrotic changes in a dose-dependent manner, as indicated by the reduced accumulation of hydroxyproline (HP). In addition, FTS suppressed BLM-induced cellular inflammatory response in the lungs, as evidenced by inhibition of increased lung weight, reduced accumulation of inflammatory leucocytes, including lymphocytes and neutrophils, but not macrophages, and less pronounced histopathological changes. Finally, BLM challenge increased the local synthesis of proinflammatory cytokines, TNF-alpha and IL-1beta and chemokines, MCP-1, MIP-1alpha RANTES, MIP-2 and KC, while administration of FTS suppressed the production of these cytokines, except for MCP-1. These effects of FTS were observed only when mice received intratracheal instillation with BLM. Considered collectively, our results indicated that FTS treatment ameliorated the cellular inflammatory responses and fibrotic changes in the lungs caused by BLM and such inhibition was well correlated with reduced synthesis of several fibrosis-related cytokines, and suggested that FTS may be potentially useful for the treatment of pulmonary fibrosis.

Animals↗
PubMed2006

[Changes of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in the bronchoalveolar lavage fluid and the serum of patients with idiopathic pulmonary fibrosis].

OBJECTIVE: To detect the levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the bronchoalveolar lavage fluid (BALF) and the serum of patients with idiopathic pulmonary fibrosis (IPF), and to evaluate the significance of the changes in the pathogenesis of IPF. METHODS: Enzyme-linked immunoadsorbent assay (ELISA) was used to detect MMP-9 and TIMP-1 in the BALF and serum of 30 patients with IPF. RESULTS: The levels of MMP-9 in the BALF and serum of the patients showed no significant difference as compared with those of the control group. The levels of TIMP-1 in the BALF [(522 +/- 81) ng/L] and serum [(166 +/- 29) ng/L] of the patients were higher than those [(201 +/- 31), (87 +/- 16) ng/L] of the control group (P < 0.01). The ratios of MMP-9/TIMP-1 in the BALF (0.53 +/- 0.18) and serum (1.5 +/- 0.3) of patients with IPF were lower than those (1.06 +/- 0.38, 2.6 +/- 0.5) of the control group (P < 0.01, < 0.05). TIMP-1 in the BALF of the patients showed a strong positive correlation with chest CT fibrosis and pulmonary function test scores (P < 0.01), while MMP-9/TIMP-1 in the BALF had negative correlation with them (P < 0.01). CONCLUSION: Pulmonary fibrosis may be associated with increased TIMP-1 and decreased MMP-9/TIMP-1, which is able to inhibit the degradation of extracellular matrix.

Adult↗
PubMed2005

Murine candidate bleomycin induced pulmonary fibrosis susceptibility genes identified by gene expression and sequence analysis of linkage regions.

BACKGROUND: Pulmonary fibrosis is a complex disease for which the predisposing genetic variants remain unknown. In a prior study, susceptibility to bleomycin induced pulmonary fibrosis was mapped to loci Blmpf1 and Blmpf2 on chromosomes 17 and 11, respectively, in a C57BL/6J (B6, susceptible) and C3Hf/KAM (C3H, resistant) mouse cross. METHODS: Herein, the genetic basis of bleomycin induced pulmonary fibrosis was investigated in an approach combining gene expression and sequencing data with previously mapped linkage intervals. RESULTS: In this study, gene expression analysis with microarrays revealed 1892 genes or ESTs (expressed sequence tags) to be differentially expressed between bleomycin treated B6 and C3H mice and 67 of these genetic elements map to Blmpf1 or Blmpf2. This group included genes involved in an oxidative stress response, in apoptosis, and in immune regulation. A comparison of the B6 and C3H sequence, for Blmpf1 and Blmpf2, made using the NCBI database and available C3H sequence, revealed approximately 35% of the genes in these regions contain non-synonymous coding sequence changes. An assessment of genotype/phenotype correlation among other inbred strains revealed 36% of these B6/C3H sequence variations predict for the known bleomycin induced fibrosis susceptibility of the DBA (susceptible) and A/J (resistant) mouse strains. CONCLUSIONS: Combining genomics approaches of differential gene expression and sequence variation potentially identifies approximately 5% the linked genes as fibrosis susceptibility candidate genes in this mouse cross.

Animals↗
PubMed2004

CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling.

Aberrant vascular remodeling is a central hallmark for the development and progression of idiopathic pulmonary fibrosis. The mechanisms underlying the pathophysiologic alterations, however, are poorly understood. A recent phase II trial of interferon gamma-1b has demonstrated a trend toward a decrease in profibrotic and proangiogenic biologic markers, and upregulation of lung CXCL11 mRNA and bronchoalveolar lavage fluid and plasma protein levels of CXCL11. We hypothesized that net aberrant vascular remodeling seen during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-induced pulmonary fibrosis can be attenuated by treatment with the angiostatic ELR(-) CXC chemokine, CXCL11. In a preclinical model, systemic administration of CXCL11 reduced pulmonary collagen deposition, procollagen gene expression, and histopathologic fibroplasia and extracellular matrix deposition in the lung of bleomycin-treated mice. CXCL11 treatment significantly reduced bleomycin-induced pulmonary fibrosis without altering specific lung leukocyte populations. CXCR3 is not expressed on fibroblasts and CXCL11 had no direct functional effect on pulmonary fibroblasts. The angiogenic activity in the lung was significantly decreased, however, and CXCL11 treatment reduced the total number of endothelial cells in the lung following bleomycin exposure. The results suggest that CXCL11 inhibits pulmonary fibrosis by altering aberrant vascular remodeling.

Angiogenesis Inhibitors↗
PubMed2004

[The changes of expression level of matrix metalloprotease 9 and its inhibitor (TIMP-1) in murine pulmonary fibrosis model].

AIM: To evaluate the balance between matrix metalloprotease-9 (MMP-9) and its inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1) in bleomycin-induced pulmonary fibrosis in mice. METHODS: Pulmonary fibrosis model was induced by bleomycin in mice. The histological images of lungs were studied by HE staining. Alveolar macrophages(AMs) were separated by anti-CD68 mAbs using immunomagnetic beads(d</=50 nm). The purity of AMs was determined under microscope. Cell viability was evaluated by staining with Hoechst 33258 dye. The secreted MMP-9 and TIMP-1 were assayed in macrophage supernatants, using quantitative enzyme-linked immunosorbent assays (ELISA). RESULTS: Collagen deposition was gradually increased in the lung tissue of mice on day 1, 3, 7, 14 and 28 after bleomycin treatment. The purity of AMs could be increased from (82.5+/-2.5)% to (99.3+/-0.7)% by mini-magnetic cell sorting system (mini-MACS, P<0.05), and the rate of living cells post-MACS was (92.5+/-1.8)% (pre-MACS (92.7+/-2.0)%, P>0.05). The concentration of MMP-9 secreted by AMs was gradually decreased on day 1, 3, 7, 14 and 28, and levels of TIMP-1 gradually increased. CONCLUSION: There was an imbalance between macrophage-derived MMP-9 and TIMP-1 in bleomycin-induced pulmonary fibrosis in mice.

Animals↗
PubMed2005

Impact of recipient age and procedure type on survival after lung transplantation for pulmonary fibrosis.

BACKGROUND: The decision to perform single-lung (SLT) or bilateral sequential lung (BSLT) transplantation in patients with pulmonary fibrosis is controversial. Some centers use recipient age (<50 years) as a criterion to select BSLT over SLT, but the rationale for this approach is not well established. METHODS: Eight hundred twenty-one patients (636 SLT, 185 BSLT), aged 30 to 69 years, who were recipients of transplants for pulmonary fibrosis in the United States between 1994 and 2000 were reported to the United Network for Organ Sharing. Survival was compared by procedure type within three age groups (30 to 49 years, 50 to 59 years, and 60 to 69 years) using the Kaplan-Meier method. Multivariate logistic regression analysis was used to calculate risk-adjusted mortality within 1-month after transplantation, and proportional hazards regression was used to calculate risk-adjusted mortality after 1 month. RESULTS: Early (1-month) and late (3-year) survival in recipients aged 30 to 49 years was significantly better with SLT than BSLT (early, 90.9% versus 77.1%; late, 63.8% versus 46.2%, respectively; p = 0.02). Survival was also significantly better with SLT than BSLT at these time points in those patients aged 50 to 59 years (early, 89.5% versus 81.7%; late, 53.6% versus 46.7%, respectively; p = 0.03). When posttransplant survival was reanalyzed contingent on survival to 1 month, no significant difference in survival by procedure type (SLT versus BSLT) was detected for any age group. Multivariate analysis of survival, adjusted for other known risk factors, as well as propensity analysis, yielded similar results. CONCLUSIONS: Patients younger than 60 years of age who were recipients of transplants for pulmonary fibrosis appear to have better survival with SLT than with BSLT. Although the basis for this observation is unclear, events occurring in the early period (first month) after transplantation may play a role. Further studies will be needed, but these data do not appear to support the preferential use of BSLT for younger patients with pulmonary fibrosis.

Adult↗
PubMed1997

[Changes of extracellular matrix components in bronchoalveolar lavage fluid in patients with idiopathic pulmonary fibrosis].

To clarify the roles of extracellular matrix in pulmonary fibrosis, we determined the levels of fibronectin (FN), hyaluronan (HA) and procollagen III (PC III) in peripheral blood and in bronchoalveolar lavage fluid (BALF) in 13 patients with idiopathic pulmonary fibrosis (IPF) and 11 normal subjects. The levels of FN, HA and PC III in BALF in patient group were not only significantly higher than those in own peripheral blood, but also significantly higher than those in BALF in control group. In patient group, the levels of FN and HA in BALF were respectively correlated with total cell numbers and neutrophils. PC III levels were related to alveolar macrophages. Also, there were positive correlation between FN, HA and PC III in BALF. These results suggested that the productions of FN, HA and PC III within the lung in IPF were increased and that the levels of FN, HA and PC III in BALF might reflect the activity of the disease from different aspects and play a role in estimating prognosis.

Adult↗
PubMed2006

Receptor-activated Smad localisation in bleomycin-induced pulmonary fibrosis.

BACKGROUND: Recent advances in fibrosis biology have identified transforming growth factor (TGF)-beta type I receptor-mediated activation of Smads as playing a central part in the development of fibrosis. However, to date, there have been few studies that examined the localisation and distribution of receptor-activated Smads protein (R-Smads: Smad2 and 3) during the fibrosis progression. AIMS: To histopathologically assess the time-course change of the localisation and distribution of the Smads protein in pulmonary fibrosis. METHODS: Pulmonary fibrosis was induced by intranasal injection of bleomycin (0.3 U/mouse). Lungs were isolated 2, 5, 7, 9 and 14 days after bleomycin treatment. Histological changes in the lungs were evaluated by haematoxylin-eosin stain or Masson's trichrome stain, and scored. TGF-beta1, Smad3 and phosphorylated Smad2 localisations in lung tissues were determined by immunohistochemistry. RESULTS: The bleomycin treatment led to considerable pulmonary fibrotic changes accompanied by marked increase in TGF-beta1 expression in infiltrating macrophages. With the progression in fibrosis (day 7-14), marked increases in Smad3-positive and pSmad2-positive cells were observed. There were intense Smad3-positive and pSmad2-positive signals localised to the nuclei of the infiltrating macrophages and to type II epithelial cells, and less intense signals in fibroblasts and hyperplastic alveolar/bronchiolar epithelial cells. CONCLUSIONS: The time-course data of TGF-beta1 and R-Smads indicate that progressive enhancement of TGF-beta1 signalling via R-Smad is activated in the process of fibrosis progression.

Animals↗
PubMed1988

Pregnancy in a woman with severe pulmonary fibrosis secondary to hard metal disease.

The effect of interstitial pulmonary fibrosis on pregnancy is unclear. We present the findings in a 31-year-old woman with severe pulmonary fibrosis (vital capacity, 37 percent of predicted) secondary to hard metal disease who went through a successful term pregnancy. The patient was a grinder of tungsten-carbide drill bits who developed pneumonitis and subsequent fibrosis. Her therapy required steroids and cyclophosphamide for stabilization of her pulmonary function prior to her pregnancy. At six months' gestation, right heart catheterization showed normal cardiac output and pulmonary arterial and wedge pressures. Stage 2 exercise study demonstrated a maximum oxygen consumption of 1.17 L/min (53 percent of predicted). The patient was able to exercise to a maximum workload of 300 kpm/min (32 percent of predicted). She became hypoxemic (arterial oxygen pressure, 54 mm Hg) at 150 kpm/min. Her pregnancy concluded with an uncomplicated normal vaginal delivery requiring only supplemental oxygen and spinal anesthesia. Review of the few similar cases suggests that a woman can have a successful pregnancy despite severe pulmonary dysfunction.

Adult↗
PubMed1980

Pulmonary fibrosis, carcinoma, and ferruginous body counts in amosite asbestos workers. A study of six cases.

The Tyler Asbestos Workers Program is a continuing study of 1,105 former amosite asbestos workers. This report includes a study of six former workers, five of whom died and had autopsies, and one who underwent a lobectomy. Five of these men were exposed to asbestos for three months or less. Four had lung cancer, and one a rectal carcinoma. All were cigarette smokers. Ferruginous (asbestos) body content of the upper and lower lobes of the lungs was quantitated by a digestion technic. Tissue sections from upper and lower lobes were independently quantitated for fibrosis and ferruginous bodies, and chest roentgenograms were examined for interstitial fibrosis. (Control lung tissue was obtained from consecutive autopsies of 52 adults who did not have a known occupational exposure to asbestos.) Relatively low ferruginous body counts (less than 700/g lung tissue) were associated with mild degrees of fibrosis, and higher counts (greater than 10,000/g) with moderate to severe fibrosis. Mild to moderate pulmonary fibrosis could be identified on tissue sections before interstitial changes were detectable by chest roentgenograms.

Aged↗
PubMed1976

Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects.

Idiopathic pulmonary fibrosis is a fatal disorder that starts as an alveolitis and progresses to interstitial fibrosis. Correlative morphologic, physiologic, and biochemical studies in 29 patients have shown that the inflammatory process in best followed by serial bronchoalveolar lavage and 67 Ga citrate scanning, and the fibrotic process is best followed by quantitation of the exercise-induced drop in arterial oxygen tension per unit of oxygen consumed. Although biopsies in idiopathic pulmonary fibrosis seem to show increased amounts of fibrotic tissue, biochemical studies suggest that the disease is probably one of collagen rearrangement rather than collagen increase. Perhaps becasue of this, peripheral lymphocytes of these patients recognize collagen as "non-self" and, when exposed to it in vitro, produce lymphokines and cell lysis. The fibrotic process is probably irreversible, but the inflammatory and immune processes that cause it may be amenable to therapy if diagnosed early.

Adult↗
PubMed2004

Idiopathic pulmonary fibrosis: current trends in management.

Idiopathic pulmonary fibrosis (IPF) is a chronic scarring illness limited to the lung and characterized by progressive dyspnea, restrictive pulmonary physiology, and radiographic diffuse lung disease. During the past few years, significant progress has been made, particularly in diagnosis: a stricter case definition has been outlined by consensus among international experts. Insights into the pathophysiology have revealed novel areas for therapeutic intervention. These advances have helped clarify many important diagnostic and therapeutic issues in this disease. An effective treatment regimen is yet to be determined. Significant new insights in the natural course and monitoring disease course have provided use of appropriate endpoints to test the safety and efficacy of new treatment regimens. Several multicenter clinical trials are underway and several more are being planned. It is hoped that ongoing molecular genetic studies and results of clinical trials will improve outcome of patients and families affected with this disease in the near future.

Chronic Disease↗
PubMed2005

Interferon gamma-1b in the treatment of idiopathic pulmonary fibrosis.

OBJECTIVE: To examine the clinical aspects of idiopathic pulmonary fibrosis (IPF) and the efficacy and safety of interferon gamma-1b (IFNgamma-1b) in its treatment. DATA SOURCES: Epidemiologic, preclinical, and clinical studies published in the English language were identified by a MEDLINE search (1966-January 2005) using the search terms idiopathic pulmonary fibrosis, cryptogenic fibrosing alveolitis, and interferon. Additional citations were identified from the reference lists of related publications. STUDY SELECTION AND DATA EXTRACTION: Selected preclinical studies describing the pathophysiologic basis for IFNgamma-1b therapy and all clinical studies were included. Additional trials describing other treatment modalities and the determinants of response to therapy in patients with IPF were also reviewed. DATA SYNTHESIS: IFNgamma-1b targets the fibrotic rather than inflammatory processes of IPF. The efficacy of IFNgamma-1b in patients with IPF is inconsistent with regard to changes in pulmonary function and mortality, although a modest survival benefit was observed in the largest clinical trial. Adverse events related to IFNgamma-1b are frequent although transient. Several cases of respiratory failure occurring subsequent to the administration of IFNgamma-1b are documented. CONCLUSIONS: To date, although trials suggest that earlier-stage IPF may be responsive to IFNgamma-1b, study results overall are inconsistent; further investigation is needed.

Clinical Trials as Topic↗
PubMed1996

[Using ligustrazini and angelica sinensis treat the bleomycin-induced pulmonary fibrosis in rats].

OBJECTIVE: To seek a kind of Chinese traditional medicine to treat the bleomycin-induced pulmonary fibrosis. METHODS: SD rats with bleomycin A(s) induced pulmonary fibrosis, were divided into 4 groups. Normal control group (10 rats), untreated model group (35 rats), ligustrazini group (10 rats), Angelica sinensis group (10 rats). Both ligustrazini and angelica sinensis were given intraperitoneally by injection daily for 28 days. Then all rats were put to death and took out the lungs for examination. Using histopathological examination and image processing computer assisted to evaluate the result of treatments. RESULTS: Ligustrazini could obviously reduced alveolitis and fibrosis and Angelica sinensis had the similar but lesser result. CONCLUSION: Ligustrazini and angelica sinensis have successful result of treatment for pulmonary fibrosis.

Animals↗