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Idiopathic pulmonary fibrosis (IPF) proved by lung biopsy occurred in a pair of monozygotic twin brothers who had lived apart for many years. Histopathology of the two cases was almost identical. The purpose of this report is to substantiate the role of genetic factors in the development of IPF.
The incidence of lung cancer in patients with idiopathic pulmonary fibrosis is much higher than that in general population. We report on a case of large cell carcinoma in association with the additional occurrence, seven months later, of an adenocarcinoma of the lung. Surgical treatment was performed for each cancer, however, the outcome was poor. The association between the two disorders is discussed.
In a 70 years old worker in the bauxite industry in Surinam, who died of myocardial infarction, bauxite deposits were found in the lung in areas of mild pulmonary fibrosis. The identification and the localization within these areas of the bauxite deposits was determined by a histochemical mineralization technique and by scanning electron microscopy and electron microprobe analysis. The possible relationship between the presence of bauxite in the lung tissue and the pulmonary fibrosis is discussed.
This paper describes 20 cases of idiopathic diffuse interstitial pulmonary fibrosis. The clinical manifestations are dry cough, chronic progressive dyspnea, clubbed fingers and velcros rales. CT (HRCT) scanning were performed in 8 patients and the results were compared with the common X-ray chest films, the images of HRCT were more clearer than common chest films, the fine grain shadows, which can not be shown on the common X-ray chest films, were shown on HRCT. The final diagnosis is based on the transbronchial lung biopsy or open lung biopsy.
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We investigated lung cancer in 99 patients with idiopathic pulmonary fibrosis (IPF). Lung cancer was found in 31 (31.3%) of 99 patients with IPF. Most (87.9%) tumors, including squamous cell carcinoma, were observed in the peripheral region of the lung, whereas the distribution of histologic types of cancers was similar to that seen in ordinary lung cancer. Peripheral tumors were frequently seen in the lower lobe, where fibrotic shadow was prominent. However, the severity of fibrosis was not related with the prevalence or histologic type of lung cancer. Two-thirds of IPF patients having a smoking history of over 40 years developed lung cancer. When compared with nonsmoking IPF control subjects, the relative risk of smoking in IPF patients was 3.5, identical with that reported for smokers in the general population. We suggest that smoking in patients with IPF is an additive risk factor for the development of lung cancer. We also speculate that the high prevalence of peripheral squamous cell carcinoma might be associated with cigarette smoking.
Modulation of cytokine expression represents a potentially useful approach for the treatment of idiopathic pulmonary fibrosis (IPF). To identify potential targets for such intervention, semi-quantitative reverse transcriptase-polymerase chain reaction was used to compare the expression of messenger ribonucleic acids (mRNAs) coding for 17 cytokines in lung tissue obtained from patients with IPF at the time of diagnosis and control subjects. Some cytokines were also studied at the protein level by immunohistochemical techniques. mRNAs coding for all of the cytokines evaluated were detected in both control and fibrotic lung samples. Only transforming growth factor (TGF)-beta and interleukin (IL)-10 mRNAs were quantitatively increased in lung biopsies from patients with IPF compared with those of controls, results confirmed at the protein level by immunohistochemistry. Although mRNAs for platelet-derived growth factor (PDGF)-BB and keratinocyte growth factor (KGF) were expressed in similar amounts in lungs from patients with IPF and controls, localised accumulation of both factors was also observed in IPF. Hyperplastic alveolar epithelial cells were a prominent source of cytokines, where IL-10, PDGF-BB and KGF were present in increased amounts, although increased accumulation in fibroblasts, smooth-muscle cells and matrix components was also observed (PDGF-BB, TGF-beta). These results offer new insights into the cytokines produced in the lung in idiopathic pulmonary fibrosis and suggest that modulation of the production of transforming growth factor-beta and interleukin-10 may represent a potentially useful therapeutic strategy for this disabling disease.
The treatment of idiopathic pulmonary fibrosis (IPF) remains controversial. The benefits of conventional treatment with corticosteroids plus either azathioprine or cyclophosphamide have not been established in randomized, controlled trials. Other treatment strategies have been suggested as understanding of the pathogenesis of IPF has increased. Recent clinical and animal studies suggest that modulating the effects of profibrotic growth factors and cytokines holds significant promise. As additional well controlled prospective studies are completed, these trials should provide the clinical evidence necessary for identifying optimal treatment strategies for future patients who have IPF.
The objective of this study was to evaluate the effectiveness of erythromycin (EM) on bleomycin-induced pulmonary fibrosis in rats and its possible mechanisms. Seventy-five rats were divided into three groups. Alveolar macrophages (AM) were harvested through bronchalveolar lavage (BAL) and consecutive changes of tumour necrosis factor-alpha (TNF-alpha) and platelet-derived growth factor (PDGF) in AM supernatant and bronchoalveolar lavage fluid (BALF) were assayed with ELISA and bioassay, respectively. The AM-derived TNF-alpha was elevated on day 3, peaked day 7 and then decreased but remained at higher level until day 28. The AM-derived PDGF was increased on day 3, peaked on day 7 then decreased to non-statistically significant higher level. The TNF-alpha in BALF was increased significantly on day 3 then decreased to normal level; the peak preceded that of AM-derived TNF-alpha. The PDGF in BALF was increased on day 3, peaked on day 7, and then decreased to normal, which exhibited a consecutive change similar to that of AM-derived PDGF. The EM significantly suppressed TNF-alpha and PDGF release by AM, markedly decreased TNF-alpha and PDGF levels in BALF. The EM also lessened the collagen deposition, the lung hydroxyproline comprised 75.44%, 72.72% and 56.24% that of bleomycin-treated group on day 7, 14 and 28, respectively. In conclusion, EM can ameliorate bleomycin-induced pulmonary fibrosis possibly through suppression of TNF-alpha and PDGF as well as the inhibition on accumulation of inflammatory cells in the lung.
Eosinophils have been shown to increase in tissues during many fibrotic conditions and consequently have been suggested to contribute to the development of fibrosis. This study tested the hypothesis that eosinophils are essential in the development of lung fibrosis in mice in response to bleomycin (BLM). Anti-IL-5 antibody was administered intraperitoneally into mice 2 h prior to endotracheal BLM inoculation and thereafter, every other day. Lung eosinophilia was evaluated by measurement of eosinophil peroxidase activity and confirmed by eosinophil counts in histologic sections. Lung fibrosis was evaluated by hydroxyproline content and confirmed by collagen staining in histological sections. Results demonstrated that BLM induced pronounced lung eosinophilia, which was maximal 7 days after BLM treatment and remained elevated through day 14, in C57B1/6 SCID mice and CBA/J mice. In contrast, eosinophilia was a minor component in the lungs of wildtype C57B1/6 mice after BLM treatment, although lung fibrosis developed similarly in all three strains of mice. Treatment with anti-IL-5 completely abrogated eosinophilia but failed to block pulmonary fibrosis induced by BLM in all mouse strains, including C57B1/6 SCID, wildtype C57B1/6 mice, and CBA/J mice. Analysis of cytokine mRNA by RNase-protection assay in C57B1/6 SCID mice indicated that BLM treatment caused enhanced expression of the cytokines, TNF-alpha, and IL-6 at days 3, 7, and 14 post-BLM inoculation, regardless of whether eosinophils were depleted by anti-IL-5. Finally, the importance of eosinophils in lung fibrosis was examined in IL-5 gene knockout mice (IL-5tm1Kopf). BLM treatment induced significant lung fibrosis in IL-5 knockout mice in the absence of eosinophilia. These findings indicate that eosinophils are not an absolute requirement for BLM-induced pulmonary fibrosis in the mouse.
BACKGROUND: The prognosis of pulmonary fibrosis associated with scleroderma (PF-SSc) has been reported to be significantly better than that of IPF. Because the nonspecific interstitial pneumonia-pattern (NSIP), a newly defined subgroup of idiopathic interstitial pneumonias (IIP), has better prognosis than the usual interstitial pneumonia pattern (UIP), we postulated that NSIP may occur more frequently than UIP in patients with scleroderma who develop fibrosis. METHOD: We reviewed the pathologic, radiologic and clinical outcomes in 19 patients with PF-SSc. Two pulmonary pathologists reclassified the histopathology of surgical lung biopsies (SLBx) and consensus diagnosis was achieved in all patients. RESULTS: Thirteen patients had NSIP, five had UIP, and remained one showed only nondiagnostic honeycombing. No significant difference was noted in the initial pulmonary function test (PFT), bronchoalveolar lavage (BAL) findings, or other clinical parameters between UIP and NSIP groups. Comparison of the clinical outcome of 12 patients who were followed for more than 12 months (mean: 34.5 +/- 26.0 months) suggested a better prognosis for NSIP than UIP. Five of the eight NSIP patients improved and three were stable, whereas in patients with UIP, one worsened and three were stable. CONCLUSION: NSIP seems to be the major histopathologic pattern in patients with PF-SSc.
OBJECTIVE: To identify distinguishing characteristics between patients with idiopathic pulmonary fibrosis (IPF) and primary lung carcinoma and patients with either IPF or carcinoma alone. PATIENTS AND METHODS: The study group consisted of 24 patients with histologically proven usual interstitial pneumonia and lung carcinoma identified through a search of the Rochester Mayo Clinic database for 1990 to 1998. Medical records, radiographs, and histological slides were reviewed. Several variables including survival were compared in 2 control groups, IPF only and carcinoma only, by using various statistical methods. RESULTS: Our study group included 21 men and 3 women (mean age, 72.3 years). Twenty-two were past or current smokers. Approximately half of the lung carcinomas were incidental findings. Of the 14 patients with preoperative computed tomographic scans, 12 had peripheral tumors situated in areas of fibrosis. Squamous cell carcinoma was the most common histological type, accounting for 16 cases. Almost all patients underwent surgical treatment; nearly 40% developed postoperative complications, and 3 died within 30 days of surgery. The ratio of men to women in patients with IPF and carcinoma was 7:1 compared with 1:1 in patients with IPF only (P=.003). Patients with IPF and carcinoma were also older, with a mean age of 72.3 years compared with 64.4 years (P=.001), and were more often smokers (P=.002). Carcinomas involved the lower lobes in 42% of patients with IPF and carcinoma compared with 29% of patients with carcinoma only (P=.004) and were mainly composed of squamous cell carcinoma (P=.004). Mean survival in patients with IPF and lung carcinoma was 2.3 years after the diagnosis of IPF and 1.6 years after that of carcinoma. This finding did not differ significantly from survival of patients with either IPF or carcinoma alone. However, statistical power was limited. CONCLUSION: Carcinoma in patients with IPF arises in older male smokers and usually presents as peripheral squamous cell carcinoma. The prognosis is poor.
OBJECTIVE: Patients with interstitial pulmonary fibrosis (IPF) often have diffusely abnormal findings on chest radiographs, making it difficult to detect evidence of superimposed congestive heart failure (CHF) or pneumonia. The goal of this study was to determine whether the crackles of IPF differed in their transmission and frequency from crackles of CHF and pneumonia in the hope of improving diagnosis and monitoring of these patients. METHODS: A multichannel lung sound analyzer was used to collect 20-s samples of sound from 25 patients with pneumonia, 17 patients with CHF, and 19 patients with IPF. We calculated a crackle transmission coefficient (CTC) by quantifying the distance a crackle spreads using a technique that cross-correlated the signal containing the highest amplitude crackle with the corresponding signal on all other ipsilateral channels: CTC, 0% = no transmission; CTC, 100% = equal transmission to all channels. RESULTS: Both the CTC and the crackle frequency in IPF were statistically different from that in CHF and pneumonia (p < 0.0001). The CTC averaged 24 +/- 5% for pneumonia, 25 +/- 8% for CHF, and 14 +/- 4% for IPF. The crackle frequency averaged 302 +/- 47 Hz for pneumonia, 311 +/- 62 Hz for CHF, and 462 +/- 50 Hz for IPF (+/- SD). CONCLUSION: These differences in CTC and crackle frequency offer the promise of helping guide treatment in IPF patients.
Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and typically fatal interstitial lung disease. Besides its grave natural history and prognosis, three aspects of IPF challenge clinicians and investigators: (1) recent changes in the conceptual framework and definition of IPF complicate interpretation of prior clinical investigations; (2) while most patients with suspected IPF do not undergo open-lung biopsy, clinical definitions that do not include biopsy criteria have not been validated prospectively; and (3) available treatments have not been shown to be effective. To optimize clinical care and facilitate clinical investigation, a major goal of IPF research should be to develop validated sets of clinical diagnostic and prognostic criteria. Studies have shown the diagnostic value of high-resolution CT scans and identified important prognostic variables; many of these observations await prospective validation. While previous therapeutic studies have been limited by small sample sizes, lack of a placebo control group, and insufficient attention to patient-centered outcomes, the recent study of interferon gamma-1b demonstrated the feasibility of a large-scale, multicenter clinical trial in IPF. In this article, we discuss how overcoming challenges in IPF research will enable future investigators to conduct well-designed observational studies and clinical trials, whose meaningful results will advance our understanding of IPF, its management, and its impact on patients' lives.
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine involved in controlling critical cellular activities including proliferation, differentiation, extracellular matrix production, and apoptosis. TGF-beta signals are mediated by a family of Smad proteins, of which Smad2 and Smad3 are downstream intracellular targets of serine/threonine kinase receptors of TGF-beta. Although Smad2 and Smad3 are crucial for TGF-beta signaling, little is known about the regulation of their expression. In this study, we investigated the expression of Smad2 and Smad3 in an in vivo animal model of lung fibrosis induced by bleomycin. We found that the expression of Smad3 was regulated in lungs during bleomycin-induced pulmonary fibrosis. The decline of Smad3 mRNA was evident at day three of post-bleomycin instillation and the expression of Smad3 continually decreased during the reparative phase of lung injury (days 8 and 12), whereas the expression of Smad2 showed little change after bleomycin administration. We further investigated whether the expression of Smad3 was regulated by TGF-beta in an in vitro lung fibroblast culture system. Our results show an immediate translocation of Smad3 protein from the cytoplasm to the nucleus and a delayed down-regulation of Smad3 mRNA by TGF-beta in lung fibroblasts. These studies provide direct evidence for a differential regulation of Smad3 expression that is distinct from that of Smad2 during bleomycin-induced pulmonary fibrosis and suggest a ligand-induced negative feedback loop that modulates cellular TGF-beta signaling.
Lung volumes and volume pressure (V-P) relationships were measured in anesthetized hamsters 8, 30, 60, and 90 days after induction of interstitial pulmonary fibrosis by intratracheal administration of bleomycin. Subsequently, total collagen, elastin, protein, deoxyribonucleic acid (DNA), and dry weight were determined in the lungs of each animal. The mean volume of air in the lungs at a transpulmonary pressure of 25 cm H2O and mean quasi-static compliance were decreased at 8 and 30 days and had returned toward normal by 60 and 90 days. Dry lung weight and total protein content were increased at 8 days, peaked at 30 days, and were still greater than normal at 90 days; DNA peaked at 8 days, remained unchanged through day 60, and returned to normal by day 90. Collagen and elastin content, although not significantly different from control at day 8, was increased at day 30 with peak values attained at day 90. Ratios of collagen or elastin to dry weight, total protein, and DNA were decreased at 8 days, normal at 30 days, and increased at 90 days. The ratios of collagen or elastin to total protein, dry lung weight, or DNA cannot be used as indicators of the amounts of these proteins in the whole lung. We conclude that in interstitial pulmonary fibrosis induced with bleomycin the pattern of changing biochemical composition of the lungs cannot be inferred from the lung volumes or V-P relations.
The effects of isoliensinine (IL), a bisbenzylisoquinoline alkaloid extracted from the Chinese traditional medicine seed embryo of Nelumbo nucifera Gaertn., on bleomycin (BLM)-induced pulmonary fibrosis in mice were investigated. Seventy-two male Kungming mice were divided randomly into eight groups as BLM-IL10, BLM-IL20, BLM-IL40, BLM-Sal, Sal-IL10, Sal-IL20, Sal-IL40 and Sal-Sal groups. BLM (0.1 mg in 0.05 ml saline per animal, once) or saline (0.05 ml per animal, once) was applied intratracheally, and IL (10, 20, 40 mg/kg) or saline was administered orally 3 times per day in the appropriate groups. Animals were sacrificed 14 days after intratracheal treatment. Lung tissue and serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta 1 (TGF-beta (1)) were determined by biochemical measurements and immunohistochemistry. BLM treatment resulted in a significant increase of the hydroxyproline content and an obvious lung histological injury as compared to the Sal-Sal group. Administration of IL remarkably suppressed the increase in hydroxyproline content and abated the lung histological injury induced by BLM. There was a decrease in SOD activity and an increase in MDA level in lung tissue and serum in the BLM-Sal group (p < 0.01 , p < 0.01, vs. Sal-Sal group, respectively). And IL could obviously enhance the SOD activity and decrease the MDA level in a concentration-dependent manner. Moreover, IL also significantly inhibited the overexpression of TNF-alpha and TGF-beta (1) induced by BLM. These results indicated that IL possessed a significant inhibitory effect on BLM-induced pulmonary fibrosis, probably due to its antioxidant and/or anti-inflammatory activities and inhibitory overexpressing TNF-alpha and TGF-beta (1) induced by BLM.
This study examined the effect of the prone position on mechanically ventilated patients with hydrostatic pulmonary edema (HPE). Eight patients with acute HPE and mechanically ventilated in the prone position (Group 1) were studied. Six patients with acute HPE and mechanically ventilated in the supine position (Group 2), 20 patients with ARDS (Group 3), and 5 patients with pulmonary fibrosis (PF) (Group 4) served as control patients. Patients with HPE, who after being mechanically ventilated for at least 6 h needed an FI(O(2)) >/= 0.6 to achieve an Sa(O(2)) of approximately 90%, and did not respond to recruitment maneuvers, were turned to the prone position. Parameters of oxygenation, lung mechanics, and hemodynamics were determined in both the supine and prone positions. All patients with HPE exhibited improvement of oxygenation when they were placed in the prone position. The Pa(O(2))/FI(O(2)) ratio increased from 72 +/- 16 in the supine position to 208 +/- 61 after 6 h in the prone position (p < 0.001); the rise in Pa(O(2)) was persistent, without detrimental effect on hemodynamics. Fifteen of 20 patients with ARDS (75%) improved oxygenation when in the prone position. The Pa(O(2))/FI(O(2)) ratio increased from 83 +/- 14 in the supine position to 189 +/- 34 after 6 h in the prone position (p < 0.001). In contrast, 5 of 20 patients with ARDS (25%) and none of the patients with PF responded favorably to prone positioning. Patients with HPE and early ARDS responded better to prone positioning than did patients with late ARDS and PF. Patients with HPE and ventilated in the supine position had a lower Pa(O(2))/FI(O(2)) ratio and the duration of mechanical ventilation was longer compared with that of patients in the prone position. Our results show that the prone position may be a useful maneuver in treating patients with severe hypoxemia due to pulmonary edema. The presence of pulmonary edema, as in early ARDS and HPE predicts a beneficial effect of the prone position on gas exchange. In contrast, the presence of fibrosis, as in late ARDS and pulmonary fibrosis, predisposes to nonresponsiveness to prone positioning.