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PubMed2006

Drug-induced pneumonitis associated with imatinib mesylate in a patient with idiopathic pulmonary fibrosis.

A 74-year-old man with idiopathic pulmonary fibrosis (IPF) developed severe dyspnea on exertion after the readministration of imatinib mesylate for chronic myeloid leukemia. Chest X-ray and CT showed ground-glass opacities in both lungs in addition to preexisting honeycombing. Discontinuation of imatinib and methylprednisolone pulse therapy followed by administration of oral prednisolone resulted in improvement in both symptoms and radiographic findings. Imatinib-induced pneumonitis was diagnosed based on the clinical course and findings. Only five previous reports of imatinib-induced pneumonitis have been published in the literature, and this is the first case reported in a patient with IPF.

Aged↗

PubMed1998

Marked elevation of CA19-9 in a patient with idiopathic pulmonary fibrosis: CA19-9 as a bad prognostic factor.

A 53-year-old Japanese female, who had been suffering from idiopathic pulmonary fibrosis (IPF) for 3 years, was admitted with dyspnoea. The important laboratory finding on admission was a serum CA19-9 level of 649 U/mL. Despite steroid treatment for IPF, her respiratory condition gradually deteriorated with the increase of serum CA19-9 level up to 3020 U/mL and she died of respiratory failure. Immunohistochemistry showed the positive stain of CA19-9 in bronchoepithelial cells. We also reviewed the Index Medics and picked up the cases who had elevation of CA19-9 more than 1000 U/mL, and six patients were listed. Five of these six patients died within 6 months, therefore the marked elevation of CA19-9 seemed to be a bad prognostic factor in patients with pulmonary fibrosis.

CA-19-9 Antigen↗

PubMedDate not supplied

Response to steroid therapy in patients of idiopathic pulmonary fibrosis: a retrospective analysis.

Fifty four patients of idiopathic pulmonary fibrosis were evaluated retrospectively to see the effect of prednisolone therapy on the course of the disease. The diagnosis was established based on clinical history, physical findings, radiology, HRCT, spirometry and transbronchial biopsy whenever possible. Each patient received prednisolone 1 mg/kg/day for 6 weeks which was then tapered gradually till a maintenance dose was achieved. Six patients (11.1%) died within 3 months (3 within 1 month) of presentation because of rapid progression of the disease and inspite of addition of intravenous methyl prednisolone. Improvement in symptomatology, particularly cough and dyspnoea, were quite variable. Twenty six (48.1%) reported subjective improvement by 20-80% of the initial symptoms. However, in most cases this improvement was for the initial 3-6 months of therapy. Subsequently either they deteriorated or remained stable. There was no clinical improvement in the remaining 20 patients (improvement in symptoms by 0 to less than 20%). There was no radiological improvement in any case. FVC improved at 3 months only after treatment compared to the baseline values (p < 0.01). However, subsequently there was no significant improvement in the lung function. Of the 37 cases whose initial FVC value could be obtained, 8 patients (21.6%) showed an improvement by more than 20% of their baseline values during their follow up period. Of these, 4 had the improvement by 3 months; 3 by 6 months; and one showed improvement at 1 year and 6 months. Five patients (13.5%) had a decrease in FVC by 10% or more during their follow up. One patient developed sputum positive pulmonary tuberculosis nine months after steroid therapy.

Adult↗

PubMed2001

Corticosteroids in idiopathic pulmonary fibrosis.

Corticosteroids were the mainstay of therapy for idiopathic pulmonary fibrosis (IPF) for more than four decades, but their efficacy is unproven and toxicities are substantial. The course of IPF is characterized by progressive respiratory insufficiency, leading to death within 3 to 8 years from the onset of symptoms. Although a subset (10-20%) of patients survives more than 10 years, there is no evidence that any form of therapy alters the natural history of the disease. Nonetheless, given the poor prognosis, a trial of corticosteroids is often given. Because of the rarity of IPF, randomized, placebo-controlled therapeutic trials have not been done. Further, no studies have compared differing dosages or duration of corticosteroid in matched patients. Interpretation of therapy efficacy is obscured by several factors including heterogeneous patient populations, inclusion of patients with histologic entities other than usual interstitial pneumonia, lack of objective, validated endpoints, different criteria for "response." We review published data regarding corticosteroid therapy for IPF and present a rationale for stratifying therapy based on host, demographic, and clinical factors that influence prognosis as well as risk for corticosteroid complications.

Adrenal Cortex Hormones↗

PubMed1993

Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica.

We explored the role of interleukin 1 (IL-1) in two models of pulmonary fibrosis (PF), elicited in mice by the intra-tracheal instillation of bleomycin or silica. In both models, administration of IL-1 receptor antagonist (IL-1ra) by an osmotic minipump implanted i.p., at a rate of 0.5 microgram/h, completely prevented the collagen deposition, as evaluated by the lung hydroxyproline content on day 15 after instillation. IL-1ra had little or no influence on the number of cells recovered from the broncho-alveolar lavage. Study of histological sections suggests that IL-1ra globally decreased the proportion of damaged lung and particularly in silica the formation of nodules with a rich content in collagen fibrils. IL-1ra was also effective in reducing the lung hydroxyproline content when given on day 25 after instillation of bleomycin or silica, indicating that it may reverse established PF. This study indicates that IL-1ra might be useful for the treatment of incipient or established pulmonary fibrosis.

Animals↗

PubMed2005

Patients' perspectives on how idiopathic pulmonary fibrosis affects the quality of their lives.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with a survival of only three to five years from the time of diagnosis. Due to a paucity of studies, large gaps remain in our understanding of how IPF affects the quality of patients' lives. In only one other study did investigators ask patients directly for their perspectives on this topic. Further, currently there is no disease-specific instrument to measure health-related quality of life (HRQL) in patients with IPF. A carefully constructed measurement instrument, sensitive to underlying change, is needed for use in clinical trials and longitudinal studies of patients with IPF. Before developing such an instrument, researchers must improve their understanding of the relevant effects of IPF on patients' lives. On a broader scale, to provide the best care for people with IPF, clinicians must appreciate--from patients' perspectives--how this disease affects various aspects of their lives. METHODS: We used focus groups and individual in-depth interviews with 20 IPF patients to collect their perspectives on how IPF affects their lives (with a focus on the quality of their lives). We then analyzed these perspectives and organized them into a conceptual framework for describing HRQL in patients with IPF. Next, we examined how well certain existing measurement instruments--which have been administered to IPF patients in prior studies--covered the domains and topics our patients identified. RESULTS: In our framework, we identified 12 primary domains: symptoms, IPF therapy, sleep, exhaustion, forethought, employment and finances, dependence, family, sexual relations, social participation, mental and spiritual well-being, mortality. Each domain is composed of several topics, which describe how IPF affects patients' lives. When we compared the content of our conceptual framework with the existing instruments, we found the coverage of the existing instruments to be inadequate for several reasons, including they may tap general areas of QOL or HRQL but not some areas that appear to be most directly affected by IPF, and they include items that are relevant to symptoms and effects of other respiratory diseases but not IPF. CONCLUSION: Collecting patients' perspectives and developing an organized inventory of the relevant effects of IPF on patients' lives provides valuable information for improving our understanding of the impact of this disease on patients and their loved ones. We believe our findings will help alert clinicians and researchers to IPF patients' experiences and concerns. Based on the comparison or our conceptual framework with the content of four existing instruments, it would appear that developing an IPF-specific measurement instrument is justified. Our conceptual framework for describing health-related quality of life in patients with IPF lays a solid foundation for constructing such an instrument.

Adult↗

PubMed1986

The combination of ozone and silica on the development of pulmonary fibrosis.

The biologic interactions of potentially fibrogenic agents commonly occurring as environmental pollutants remain to be rigorously characterized. Two agents that produce pulmonary fibrosis were selected for this study. Separate groups of male Sprague-Dawley rats were intratracheally instilled with 0, 2, 12, and 50 mg silica and then either sham-exposed or exposed to 0.8 ppm ozone 6 h/d, 5 d/w, for 37 exposure days. Interaction was not detected between silica and ozone in the development of pulmonary fibrosis as determined by quantitative biochemical indices (hydroxyproline and lysyl oxidase) or by histopathologic examination of the lungs. Thus, environmentally relevant levels of ozone appear unlikely to affect the progression of a concurrent silicotic lesion.

Animals↗

PubMed2005

Idiopathic pulmonary fibrosis in patients younger than 50 years.

OBJECTIVE: To assess clinical, radiological, histopathologic, and prognostic differences in younger patients with idiopathic pulmonary fibrosis (IPF). PATIENTS AND METHODS: This study consisted of patients younger than 50 years with IPF who were seen at the Mayo Clinic in Rochester, Minn, from January 1, 1994, to December 31, 2000. Clinical, radiological, and histopathologic data were abstracted from clinical records. Total lung capacity using plethysmography, vital capacity, diffusing capacity for carbon monoxide using the single-breath method, and alveolar volume using single-breath neon wash-in were measured. RESULTS: Our study population was composed of 16 men and 6 women with a median age of 45 years (range, 28-49 years). Median survival was 2.1 years, with 1- and 2-year survival rates of 68% and 53%, respectively. Of the 22 patients, 2 were current smokers, 14 were former smokers, and 6 had never smoked. Three patients had familial pulmonary fibrosis, 21 had bibasilar inspiratory crackles, and 10 had digital clubbing. Median total lung capacity was 56.2%, vital capacity was 51.0%, diffusing capacity was 45.5%, and alveolar volume was 65.0%. CONCLUSION: Although previous studies have suggested that younger age is a favorable prognostic factor in patients with IPF, we found that younger patients have the same poor prognosis as do older patients with this disorder. We observed no distinguishing differences in the clinical, radiological, and histopathologic features compared with those in older patients in whom the disorder is more common. Lung transplantation should be considered early in the treatment of younger patients with IPF.

Adult↗

PubMed1989

Acquired tracheomegaly in adults as a complication of diffuse pulmonary fibrosis.

We studied the chest radiographs of 34 consecutive patients with diffuse pulmonary fibrosis to determine the presence of tracheomegaly and to follow its progression with time. Patients had been identified by a computer search of medical records. We measured the internal transverse diameter of the trachea 2 cm above the top of the aortic arch on erect posteroanterior chest radiographs. Transverse diameters greater than 25 mm in men and 21 mm in women were considered indicative of tracheomegaly. Pulmonary-function tests, available in 30 of the 34 patients, showed restrictive lung disease. The transverse tracheal measurements were compared with the cause of fibrosis, severity of restriction, duration of illness, and other clinical variables. Tracheomegaly was present in 10 (29%) of the patients, including four with fibrosing alveolitis, four with sarcoidosis, and two with chronic progressive histoplasmosis. In seven of these patients, serial radiographs showed that the tracheal dilatation had progressed with time. Nine of 24 patients without tracheomegaly also had progressive increase in transverse tracheal diameter over time. Of the 10 patients with tracheomegaly, pulmonary-function tests were available in eight and showed moderate restrictive lung disease in six and severe restrictive lung disease in two. The duration of illness was 3-6 months in two patients, 10-22 years in five patients, and not recorded in three patients. Chronic cough and repeated respiratory infections were slightly more common in those patients with tracheomegaly than in those without. These data suggest that tracheomegaly develops as a complication of diffuse pulmonary fibrosis in patients who have at least moderate restrictive lung disease and prolonged illness, and it may have some association with chronic cough and repeated respiratory infection.

Adult↗

PubMed2001

IL-12 attenuates bleomycin-induced pulmonary fibrosis.

Interleukin (IL)-12 is a potent inducer of interferon (IFN)-gamma. We postulated that IL-12 would attenuate bleomycin-induced pulmonary fibrosis. To test this hypothesis, we administered IL-12 or murine serum albumin to bleomycin-treated mice by daily intraperitoneal injection until day 12. Mice treated with IL-12 demonstrated decreased hydroxyproline levels compared with control treated mice. Furthermore, administration of IL-12 led to a time-dependent increase in both lung and bronchoalveolar lavage fluid IFN-gamma. The antifibrotic effect of IL-12 could be attenuated with simultaneous administration of neutralizing anti-IFN-gamma antibodies. These findings support the notion that IL-12 attenuates bleomycin-induced pulmonary fibrosis via modulation of IFN-gamma production.

Animals↗

PubMed2001

Microscopic polyangiitis presenting as idiopathic pulmonary fibrosis: is anti-neutrophilic cytoplasmic antibody testing indicated?

We report a 55-year old woman with microscopic polyangiitis who presented with idiopathic pulmonary fibrosis and 1 year later developed hematuria and proteinuria. She had a high serum level of perinuclear anti-neutrophilic cytoplasmic antibodies. Renal angiogram was normal. The diagnosis of microscopic polyangiitis was confirmed by renal biopsy, which showed pauci-immune crescentic glomerulonephritis. The patient received immunosuppressive therapy and improved markedly. Consideration of small vessel vasculitis is important in the differential diagnosis of idiopathic pulmonary fibrosis.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed2000

[Idiopathic pulmonary fibrosis: from biopathology to treatment].

Alveolitis, accumulation of immune and inflammatory cells within the lower respiratory tract, is the key to the development of pulmonary fibrosis. Alveolitis is responsible for lung injury (due to release of oxidant and proteolytic enzymes) and exaggerated lung repair (due to proliferation of mesenchymal cells and imbalance of collagen synthesis). Rationale for the treatment of pulmonary fibrosis implies the knowledge of pathophysiology of the different steps of the fibrotic process.

Cell Division↗

PubMed2002

Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis.

Basic fibroblast growth factor (bFGF) is a potent mitogenic factor for smooth muscle cells, myofibroblasts, and fibroblasts, proliferation of which is a hallmark of idiopathic pulmonary fibrosis (IPF) and lymphangioleiomyomatosis (LAM). Mast cells produce bFGF and have been associated with pulmonary fibrosis. We hypothesize that smooth muscle cell/myofibroblast-like cells will be spatially associated with bFGF-containing mast cells and that bFGF receptors will be expressed on the effector cells in IPF and LAM. We performed quantitative immunohistochemistry for bFGF, mast cell tryptase, smooth muscle actin for smooth muscle cell/myofibroblast-like cells, and fibroblast growth factor receptors (Flg, Bek) and measured collagen and elastic fiber in lung sections from IPF (n = 14), LAM (n = 9), and control lung (n = 10). IPF and LAM lung contained more smooth muscle cell/myofibroblast-like cells than did control lung. bFGF-containing mast cells were abundant both in IPF and LAM and were associated with collagen, elastic fibers, and smooth muscle cell/myofibroblast-like cells in IPF. Flg was expressed on epithelial cells, endothelial cells, smooth muscle cell/myofibroblast-like cells, and macrophages in IPF. In LAM, Flg was expressed on epithelial cells adjacent to smooth muscle cell/myofibroblast-like cell aggregates. Bek was expressed dominantly on smooth muscle cell/myofibroblast-like cells in LAM and on smooth muscle cell/myofibroblast-like cells as well as neutrophils in IPF. These data suggest that mast cell-derived bFGF might exert fibrogenic, proliferative effects on smooth muscle cell/myofibroblast-like cells through its receptors.

Adult↗

PubMed1987

Disease activity in idiopathic pulmonary fibrosis: CT and pathologic correlation.

Computed tomography (CT) scans were compared with pathologic determinants of disease activity in 12 patients with idiopathic pulmonary fibrosis. The theory was that intraalveolar and interstitial cellularity would result in areas of opacification of air spaces on CT scans. All patients underwent open lung biopsy, and disease activity was assessed with a pathologic grading system. Seven patients had mild disease activity, five had moderate to marked disease activity. Opacification of air spaces was patchy in distribution, predominantly peripheral, and seen better on 1.5-mm rather than 10-mm collimation scans. Disease activity on CT scans was graded independently from 0 to 3 based on the presence and relative density of the areas of air space consolidation compared with the surrounding parenchyma. The pathologic score was significantly greater in the patients with high CT scores than in those with low CT scores (P = .001). Five patients with marked disease activity and five of seven patients with mild disease activity were correctly identified. CT may be useful in the assessment of disease activity in idiopathic pulmonary fibrosis.

Adult↗

PubMed1998

Induction of pulmonary fibrosis in organ-cultured rat lung by cadmium chloride and transforming growth factor-beta1.

Cadmium chloride (CdCl2) exposure has been reported to induce pulmonary fibrosis in rats. Accumulating evidence has shown that cytokines play a pivotal role in the excessive production of connective tissue components in pulmonary fibrosis. In this report, rat lung slice cultures were used to study the synergistic involvement of transforming growth factor-beta1 (TGF-beta1) in CdCl2-induced alveolar fibrosis. Rat lung slices were maintained at the interphase of air and medium on a polyester mesh stretched on a plastic scaffold. Treatment of lung slices with 2.5, 5 or 10 microM CdCl2 for 7 days resulted in 85, 40 and 6% respectively for relative survival. Under these culture conditions, CdCl2 alone did not induce alveolar fibrosis in rat lung slices. However, in the presence of 0.5 ng/ml TGF-beta1, CdCl2 at a dose ranging from 1 to 5 microM increased the thickness of alveolar septa. Furthermore, the thickness of alveolar septa in lung slices treated with CdCl2 was dose-dependently increased by the presence of TGF-beta1. The thickened alveolar septa were apparently due to the deposition of excessive extracellular matrix, as revealed by trichrome stain and ultrastructural examination. Our results also show that fibrogenic activity induced by the combined treatment with CdCl2 and TGF-beta1 can be reduced by co-treatment with 200 microg/ml lambda-carrageenan, a TGF-beta1 inhibitor. Therefore, the present results indicate that TGF-beta1 can synergistically stimulate the fibrogenic activity in lung tissue subsequent to CdCl2 injury.

Animals↗

PubMed1992

Haemodynamic sequelae of pulmonary fibrosis following intratracheal bleomycin in rats.

OBJECTIVE: Intratracheal instillation of bleomycin in rats has been extensively used as an animal model of pulmonary fibrosis in humans, although it produces a patchy, airway based response. We proposed that the haemodynamic sequelae of the bleomycin model might be less severe than those associated with more diffuse lung injury. METHODS: Pulmonary and systemic haemodynamic indices were examined in adult Sprague-Dawley rats (approximately 400 g, n = 10) both at rest and during submaximal exercise on a rodent treadmill, approximately 60 days after intratracheal bleomycin (6 units.kg-1), and the results compared to a control group (n = 6). RESULTS: Compared to controls, mean pulmonary artery pressure (PPA) was increased by intratracheal bleomycin (p = 0.02) both at rest [24.5 (SEM 2.6) v 18.2(0.9) mm Hg] and during exercise [34.7(3.0) v 26.7(0.7) mm Hg]. PPA-pulse product was also increased, with a similar trend in right ventricular work index, but cardiac index was not altered. Right ventricular hypertrophy was noted on necropsy examination. Consistent with pulmonary fibrosis, lung dry weight, total protein, and hydroxyproline were also raised, and these values correlated strongly with (mean) PPA at rest (r2 = 0.86, 0.81, 0.69, respectively) and during exercise (r2 = 0.81, 0.79, 0.65, respectively). Packed cell volume was increased by intratracheal bleomycin, at 49(1) v 45(1)%, p = 0.02. CaO2 tended to decrease with exercise in the bleomycin group, although this was not statistically significant, while systemic oxygen delivery and consumption were not altered. CONCLUSIONS: Pulmonary hypertension and right ventricular hypertrophy occur in this model of lung fibrosis, and correlate with the severity of fibrosis. However, these sequelae were less severe than those previously demonstrated in association with crotalaria ingestion. We suggest that the haemodynamic sequelae of the intratracheal bleomycin model are consistent with patchy, airway based fibrosis, but reflect less well the haemodynamic sequelae of more diffuse fibrotic injury associated with systemic processes.

Animals↗

PubMed2004

[Expression of Smads in lung tissue of quartz-induced pulmonary fibrosis in mice].

OBJECTIVE: To observe Smads protein expression in lung tissue of quartz exposed mice and to explore its association with pulmonary fibrosis in silicosis. METHODS: The experimental mice were divided into control and quartz groups. 0.2 g/kg weight of quartz was injected intratracheally in quartz group. Samples were collected at the 1st, 3rd, 5th, 7th, 14th and 28th day after injection. Immunohistochemical methods with quantitative image analysis were used to assay the protein expression of transforming growth factor beta(1) (TGF-beta(1)), Smad 2/3, Smad 4, and Smad 7 protein levels. Protein expression level is presented by positive unit (PU). RESULTS: Smad 2/3 protein expression increased from day 3, reaching its peak level in day 14 [(42.2 +/- 2.4) PU], and decreased gradually. The elevation of Smad 4 protein level began from day 5, and the highest degree came into day 14 [(40.0 +/- 1.8) PU], decreased thereafter. The expression of Smad 7 presented a decreasing tendency at the beginning and reaching the lowest level in day 14 [(33.5 +/- 3.3) PU]. It seemed to elevate in day 28, but was still lower than the controls. There were positive correlation between Smad 2/3, Smad 4 and TGF-beta(1) (r = 0.91, r = 0.71, respectively, P < 0.05) and also between Smad 2/3 and hydroxyproline contents of lung tissue (r = 0.85, P < 0.05) except Smad 7. CONCLUSION: Smad protein may have certain association with pulmonary fibrosis in silicosis.

Animals↗

PubMed1998

Eosinophil chemotactic activity in bronchoalveolar lavage from idiopathic pulmonary fibrosis is dependent on cytokine priming of eosinophils.

Increased numbers of eosinophils have been found in bronchoalveolar lavage (BAL) fluid obtained from patients with idiopathic pulmonary fibrosis (IPF). This suggests the presence of one or more cytokines in the lung tissue of patients with IPF, which are involved in the induction of migration of eosinophils towards the pulmonary compartment. To evaluate this hypothesis, we studied migratory responses of blood eosinophils towards BAL fluid. Migratory responses were tested by means of a modified Boyden chamber assay in 21 patients with IPF and 14 healthy controls. Experiments were performed with unprimed eosinophils and in vitro primed eosinophils (preincubated with 10(-11) M granulocyte macrophage-colony-stimulating factor). Changes in intracellular free Ca2+ ([Ca2+]i) in eosinophils in response to BAL fluid were also investigated, to characterize putative chemotaxins further. Chemotactic responses of eosinophils were observed towards BAL fluid from both patients with IPF and controls, provided that the eosinophils were primed. No changes in [Ca2+]i in eosinophils were detected in response to BAL fluid. Furthermore, neither a blocking antibody against interleukin-8 nor one against regulated on activation, normal T-cell, expressed and secreted (RANTES) influenced the response. Since a chemotactic response of in vitro primed eosinophils was also observed towards bronchoalveolar lavage fluid from normals, it was concluded, that in idiopathic pulmonary fibrosis, apart from the presence of a chemotactic factor in the lung tissue, other mechanisms such as priming of eosinophils in the peripheral blood are responsible for the extravasation of eosinophils into the pulmonary compartment. As no changes in [Ca2+]i were observed in the eosinophils after incubation with bronchoalveolar lavage fluid, the chemotaxin responsible for the migratory responses is probably not one of the known eosinophil-activating chemokines.

Adult↗