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PubMed1991

Increased expression of the interleukin-8 gene by alveolar macrophages in idiopathic pulmonary fibrosis. A potential mechanism for the recruitment and activation of neutrophils in lung fibrosis.

Neutrophil migration into the airspaces of the lung is thought to contribute to the alveolar damage and subsequent fibrosis in idiopathic pulmonary fibrosis (IPF). Interleukin 8 (IL-8), a monocyte- and macrophage-derived cytokine, displays potent chemotactic and activating properties towards neutrophils and thus may contribute to the pathogenesis of IPF. The objective of this investigation was to quantify the spontaneous expression of IL-8 transcripts by alveolar macrophages from normal healthy volunteers and individuals with IPF. A quantitative assay employing reverse transcription of mRNA and the polymerase chain reaction was utilized. The level of IL-8 mRNA in alveolar macrophages was found to be significantly elevated in individuals with lone IPF or with lung fibrosis associated with connective tissue disorders compared to normal healthy controls. Moreover, the level of IL-8 mRNA in the 23 individuals with IPF correlated with the number of neutrophils per milliliter in their bronchoalveolar lavage (BAL) and with the degree of disease severity. In addition, the level of IL-8 protein in BAL was found to reflect the pattern of IL-8 mRNA expression by alveolar macrophages. These data suggest that IL-8 derived from alveolar macrophages may significantly contribute to neutrophil involvement in the pathogenesis of IPF.

Actins↗
PubMed1999

[The mechanism and effect of erythromycin in development of pulmonary fibrosis].

OBJECTIVE: To observe the effect of erythromycin on the development of pulmonary fibrosis and explore the new therapy in pulmonary fibrosis. METHODS: By evaluating the pathologic changes, the synthesis of collagen protein, the level of activity and expression of tumor necrosis factor-alpha (TNF-alpha), the effect of erythromycin was investigated on the rat model of pulmonary fibrosis induced by bleomycin. RESULTS: The alveolitis alleviated in the first week in treatment group comparing with the control group (142.5 +/- 13.9 mg/g), the synthesis of collagen protein decreased in the fourth week treatment group (96.8 +/- 4.8 mg/g) (q Test P < 0.01). CONCLUSION: Erythromycin may alleviate the process of rat pulmonary fibrosis induced by bleomycin.

Animals↗
PubMed1988

Effects of 5 mg sublingual nitrendipine in patients with precapillary pulmonary hypertension due to pulmonary fibrosis.

In 10 patients with precapillary pulmonary hypertension due to pulmonary fibrosis, the arterial blood pressure, right heart hemodynamics, cardiac output, and arterial oxygen partial pressure were measured to evaluate the benefits of acute sublingual (5 mg) nitrendipine. Additionally, the effect of oxygen enriched air was compared to control. At rest, nitrendipine significantly diminished arterial blood pressure [102 +/- 3 to 93 +/- 3 mm Hg (mean +/- SEM)], right atrial pressure (5.7 +/- 0.9 to 3.4 +/- 0.8 mm Hg), mean pulmonary artery pressure (33.4 +/- 3.5 to 29.8 +/- 3.3 mm Hg), and pulmonary artery wedge pressure (13.0 +/- 2.0 to 6.8 +/- 0.8 mm Hg). During exercise, nitrendipine reduced mean pulmonary artery pressure (54.5 +/- 4.8 to 49.3 +/- 4.7 mm Hg) and right atrial pressure (9.3 +/- 1.3 to 6.8 +/- 1.4 mm Hg). A diminuation of arterial partial oxygen pressure did not occur at rest (63.2 +/- 3.8 mm Hg) or during exercise (50.9 +/- 5.1 mm Hg). Thus, nitrendipine causes a slight but significant improvement of right heart hemodynamics. The occurrence of arteriovenous intrapulmonary shunting due to vasodilatating effects of nitrendipine can be excluded. Also, nitrendipine can safely be used in combined arterial hypertension and pulmonary fibrosis.

Administration, Sublingual↗
PubMed1998

[Spironolactone ameliorates rat pulmonary fibrosis induced by bleomycin A5].

OBJECTIVE: The purpose of this study was to investigate the role of aldosterone in pulmonary fibrosis and the protective effect of anti-aldosterone treatment. METHOD: Rats were divided into control, fibrosis and treatment groups; rat pulmonary fibrosis was induced by endotracheal injection of bleomycin A5 and spironolactone was given 100 mg/kg daily in drinking water to treatment group. 28 days later, plasma, bronchoalveolar lavage fluid(BALF) and tissue aldosterone concentration, as well as lung collagen levels, were determined. RESULT: Plasma aldosterone was higher in fibrosis group than that in control group(469 +/- 161 pg/ml and 319 +/- 115 pg/ml, respectively), but without significant difference (P > 0.05); spironolactone could ameliorate the extent of pulmonary fibrosis, the level of lung collagen was 25% less than that of fibrosis group (3.4 +/- 0.5 mg/g lung and 4.6 +/- 1.2 mg/g lung, respectively; q = 3.7893, P < 0.05), and the level of lung protein was 22% less (50 +/- 4 mg/g lung and 65 +/- 6 mg/g lung, respectively; P < 0.01). CONCLUSION: Spironolactone had some protective effects on pulmonary fibrosis, and aldosterone might play a role in the development of pulmonary fibrosis.

Aldosterone↗
PubMed2006

Patient experiences with pulmonary fibrosis.

This survey describes the experiences of patients diagnosed with pulmonary fibrosis, focusing on the issues of patient education and resources. A survey of 52 defined-choice and open-ended questions regarding the diagnosis and management of pulmonary fibrosis was delivered. A total of 1448 respondents comprised the study group. Two-thirds of respondents reported a clear lack of information and resources on pulmonary fibrosis at the time of diagnosis. Less than half of respondents reported they felt well-informed about treatment options, the role of supplemental oxygen, pulmonary rehabilitation, and transplantation. These results suggest there is a substantial need for improved patient education regarding the diagnosis and management of pulmonary fibrosis.

Aged↗
PubMed2001

Growth factors in idiopathic pulmonary fibrosis: relative roles.

Treatment of idiopathic pulmonary fibrosis patients has evolved very slowly; the fundamental approach of corticosteroids alone or in combination with other immunosuppressive agents has had little impact on long-term survival. The continued use of corticosteroids is justified because of the lack of a more effective alternative. Current research indicates that the mechanisms driving idiopathic pulmonary fibrosis reflect abnormal, dysregulated wound healing within the lung, involving increased activity and possibly exaggerated responses by a spectrum of profibrogenic growth factors. An understanding of the roles of these growth factors, and the way in which they modulate events at cellular level, could lead to more targeted therapeutic strategies, improving patients' quality of life and survival.

Animals↗
PubMed1995

Eosinophil activation in patients with pulmonary fibrosis.

The eosinophil count and concentrations of eosinophil cationic protein (ECP) were measured in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis associated with a collagen vascular disorder (PF-CVD), sarcoidosis, and healthy controls. The patients with IPF and PF-CVD showed significant increased eosinophil count and ECP levels in BALF compared with the controls. When the patients with IPF and PF-CVD were subclassified into chronic stable, progressive, and acute progressive subgroups in accordance with the observed progression of pulmonary dysfunction during the preceding 3- to 6-month period, those in the acute progressive subgroup showed significantly elevated recovered eosinophil count and ECP level, as well as recovered lymphocyte count and total protein, albumin, and type III procollagen aminoterminal peptide-related antigens (pIIIp) in BALF, compared with either of the other two subgroups. Multivariate stepwise logistic regression analysis revealed that, among these variables, only ECP and pIIIp significantly contributed to discrimination among the three subgroups differing in disease activity. These findings suggest that eosinophils are involved in the inflammatory process in pulmonary fibrosis and that the released ECP and other cytotoxic eosinophil products may contribute to the lung injury and development of fibrosis.

Adult↗
PubMed1982

The role of soluble factors in bleomycin-induced pulmonary fibrosis.

Endotracheal administration of bleomycin causes pulmonary fibrosis characterized by increased collagen synthesis and deposition. Incubation of normal lung mince with neutral salt soluble extracts of lungs from normal and bleomycin-treated rats caused a dose-dependent inhibition of collagen and noncollagenous protein synthesis. Bleomycin-treated lung extracts, however, were significantly less effective in such inhibition when compared with normal lung extracts. This inhibitory activity was not diminished by dialysis in tubing with nominal molecular weight cutoff of 10,000 but was destroyed by heat (70 C) and trypsin digestion. This inhibitory activity could not be ascribed to residual serum or bleomycin in the lung extracts. Fractionation on Sephacryl S-200 (Pharmacia, Piscataway, NJ) showed inhibitory activity to be heterogeneous with Mr (apparent molecular weight) greater than 100,000. Extracts from spleen showed similar inhibitory activity but showed no difference in intensity between normal and bleomycin-treated spleen. These data suggest that loss or decrease in production of lung inhibitory regulatory factors is partly responsible for the noted increase in collagen production and deposition in bleomycin-induced pulmonary fibrosis.

Animals↗
PubMed2004

Effect of Feitai on bleomycin-induced pulmonary fibrosis in rats.

The current therapeutic approaches for pulmonary fibrosis, which is characterized by fibroblast proliferation and extracellular matrix remodeling, are unsatisfactory. Feitai, consisting of several herbs, is a folk formula for pulmonary tuberculosis therapy in China. To investigate the effects of Feitai on pulmonary fibrosis, Feitai was administered orally to bleomycin (BLM)-treated rats, and the lung toxicity effects were evaluated according to inflammatory cell count, protein concentration, and lactate dehydrogenase (LDH) activity in the bronchoalveolar lavage fluid (BALF), malondialdehyde level and hydroxyproline content in lung tissue 28 days post-BLM. Serial sections of the lung were stained with hematoxylin and eosin (HE) and Masson trichrome, respectively. The degree of fibrosis was assessed quantitatively using LEICA QWin image analyzer. Results showed that Feitai inhibited BLM-induced lung fibrotic lesions in a dose-dependent manner as reflected by decreased the lung hydroxyproline content and lung fibrosis fraction 28 days after BLM instillation. Treatment with Feitai also significantly ameliorated the BLM-induced lung toxicity effects detected in BALF and lung tissue. The effects in vitro on WI-38 human lung fibroblast cell line showed that Feitai significantly reduced the cell proliferation and transforming growth factor (TGF)-beta stimulated type I collagen synthesis. These results strongly demonstrate that Feitai may be useful in the treatment of pulmonary fibrosis.

Administration, Oral↗
PubMed2026

Markers of microvascular instability predict severity and survival in idiopathic pulmonary fibrosis.

INTRODUCTION: Most research on idiopathic pulmonary fibrosis (IPF) has focused on the interplay among fibroblasts, the immune system and epithelial cells. There is growing evidence that microvascular dysfunction also plays a role in disease progression, but large human translational studies are lacking. In this research, we aim to identify a proteomic signature of microvascular instability and assess the impact of current therapeutics on the microvasculature. METHODS: Olink proteomic data from patients with IPF were obtained from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) (n=914) and an independent validation cohort (n=366). Among the PFF-PR, 640 patients also have whole-blood RNA sequencing data available. A subset of 79 microvascular-associated proteins was curated, and their associations with disease severity and transplant-free survival were examined. An adaptive least absolute shrinkage and selection operator was used to generate a novel microvascular risk score. RESULTS: Higher plasma levels of five microvascular-associated proteins (SDC1, MMP10, THBS2, HGF and SERPINA5) were associated with lung function and survival in both cohorts. Whole-blood RNA sequencing of patients with microvascular risk revealed enrichment of immune-mediated processes. Patients with higher microvascular risk who were subsequently put on nintedanib in the following year had significantly better 3-year transplant-free survival compared with patients who did not receive antifibrotic intervention (HR 0.56, 95%&#x2009;CI 0.35 to 0.89, p=0.0142). DISCUSSION: Integrative multi-omics analyses suggest that perturbations to microvascular remodelling contribute to disease severity and progression in IPF. This analysis offers a framework for a precision medicine approach for IPF.

Idiopathic pulmonary fibrosis↗
PubMed2002

Universal and radiation-specific loci influence murine susceptibility to radiation-induced pulmonary fibrosis.

Susceptibility to radiation-induced pulmonary fibrosis is a heritable trait in mice. In a prior study of C57BL/6J (susceptible), C3Hf/Kam (resistant), and F1 and F2 mice derived from these strains, we estimated that approximately 38% of the measured phenotypic variation could be attributed to effects from a few genetic factors. In addition, we identified one genetic factor on chromosome 17 in the MHC region. To identify any additional genetic loci that might influence interstrain variability, we conducted a genome-wide linkage scan using 214 markers and the phenotypically extreme 94 (of 268) F2 mice. In regions exceeding suggestive linkage (LOD = 2.8), we followed up with additional markers. This scan revealed evidence for quantitative trait locus (QTL) on chromosomes 17 (LOD = 4.2), 1 (LOD = 4.5), and 18 (LOD = 3.9), which influence susceptibility to radiation-induced pulmonary fibrosis. An additional region containing a QTL on chromosome 6, LOD = 4.6, showed linkage in female mice only. The evidence for linkage to chromosome 18 weakened when it was analyzed jointly with other markers. These four loci are estimated to account for 70% of the genetic contribution to this trait with chromosome 17 and 1 accounting for 28 and 24%, respectively. To confirm and better define the influence of the chromosome 17-linked QTL on radiation sensitivity, we conducted studies on congenic mice in which the linked region on chromosome 17 had been transferred onto a B6.AKR or a C3.SW background. The chromosome 17-linked QTL was confirmed to influence the phenotype as the fibrotic radiation response of B6.AKR-H2(k) mice was significantly less than that of B6 mice (P = 0.0001). The QTL on chromosome 17 for radiation-induced lung fibrosis is within the same region as QTLs identified for lung damage after other insults, including bleomycin, ozone, and particle exposure, as well as for asthma, suggesting that this region of chromosome 17 may harbor a "universal" lung injury gene.

Animals↗
PubMed2004

Association between pulmonary fibrosis and coronary artery disease.

BACKGROUND: Pulmonary fibrosis and atherosclerosis have many similarities at the histopathologic level. Moreover, fibrotic lung diseases exhibit systemic effects and have the potential to affect the vasculature beyond the lung. The existence of a relationship between the two, however, has not been studied. METHODS: To investigate whether fibrotic lung disorders may predispose to atherosclerosis, we conducted a cross-sectional study of 630 patients referred for lung transplantation evaluation at a university hospital. We compared the prevalence of angiographic coronary artery disease (CAD) in patients with fibrotic vs nonfibrotic lung diseases. RESULTS: Fibrotic lung diseases were associated with an increased prevalence of CAD compared with nonfibrotic diseases after adjustment for traditional risk factors (odds ratio, 2.18; 95% confidence interval, 1.17-4.06). The magnitude and significance of this association were maintained when only nongranulomatous fibrotic disease or its subset, idiopathic pulmonary fibrosis, was examined. The strength of the relationship between fibrotic disorders and CAD increased when multivessel disease was analyzed (odds ratio, 4.16; 95% confidence interval, 1.46-11.9). No significant association was detected for granulomatous fibrotic disorders (odds ratio, 1.56; 95% confidence interval, 0.47-5.16; P =.47), although this subgroup had fewer cases of CAD for analysis. CONCLUSIONS: These findings support an association between fibrotic lung disorders and CAD. Further research is necessary to confirm this relationship and to explore the pathologic processes underlying, and potentially linking, these 2 conditions.

Adult↗
PubMed2005

[A preliminary study of CTGF in bleomycin-induced mouse pulmonary fibrosis].

AIM: To investigate CTGF's role in bleomycin-induced pulmonary fibrosis. METHODS: Kunming mice were intratracheally administered with bleomycin to establish pulmonary fibrosis model. The expression of CTGF was studied by immunohistochemical method and RT-PCR. The degree of fibrosis was evaluated by pulmonary hydroxyproline assay. RESULTS: CTGF protein and mRNA were not expressed in normal mice. However, they were detected in pulmonary fibrotic mice from day 7 after bleomycin treatment, and increased as fibrosis developed (P <0.01). CTGF protein's expression was correlated with hydroxyproline content in lung tissue (r=0.92, P <0.01). CONCLUSION: CTGF plays a role in pulmonary fibrosis. Detection of CTGF may be an early and sensitive marker for evaluating the occurrence and development of pulmonary fibrosis.

Animals↗
PubMed1981

The effect of indomethacin, prednisolone and cis-4-hydroxyproline on pulmonary fibrosis produced by butylated hydroxytoluene and oxygen.

The purpose of this study was to examine whether development of pulmonary fibrosis in mice could be influenced by indomethacin, prednisolone or a proline analog. Pulmonary fibrosis was produced in mice treated with butylated hydroxytoluene (BHT) 400 mg/kg and immediately exposed to 80% oxygen for 3 days. This treatment regimen resulted in 47% mortality. Surviving mice exhibited significant accumulations of pulmonary collagen as evidenced by increases in total lung hydroxyproline levels. The administration of indomethacin (4 mg/kg/day) on days 1-6 after BHT decreased mortality to 14% and diminished the accumulation of collagen in lung tissue. Indomethacin also enhanced survival when administered on days 1-3 after BHT/O2 but had no effect on lung collagen levels. Treatment with indomethacin on days 4-6 after BHT had no beneficial effect. The administration of prednisolone (60 mg/kg/day) on days 1-3, 1-6, or 4-6 after BHT decreased mortality but had no effect on accumulation of lung collagen. Cis-4-hydroxyproline (400 mg/kg/day) also had no effect on pulmonary fibrosis but did enhance survival when given on days 1-3 after BHT. Administering prednisolone (60 mg/kg/day) on days 1-6 after BHT to mice left in room air produced significantly more pulmonary fibrosis than in BHT-treated mice given saline. These data support the use of the BHT/O2 model of pulmonary fibrosis for screening potential antifibrotic agents. The possibility that corticosteroid treatment may enhance pulmonary fibrosis in a damaged lung is also demonstrated.

Animals↗
PubMed2005

Angiotensin II antagonism fails to ameliorate bleomycin-induced pulmonary fibrosis in mice.

Based on current evidence, transforming growth factor (TGF)-beta plays a central pathogenic role in the development of pulmonary fibrosis. There is growing evidence that angiotensin II can serve as a stimulus for TGF-beta-mediated lung fibrosis. However, the role of angiotensin II in the pathobiology of pulmonary fibrosis in vivo remains unclear and the therapeutic potential for targeting angiotensin II in a bleomycin-induced pulmonary fibrosis model is not well known. Therefore, the aim of this study was to test whether the angiotensin II antagonist, losartan, attenuated the development of bleomycin-induced pulmonary fibrosis in two distinct murine strains, C57/BL6 and Sv129. This was determined by histopathology and quantification of collagen content by hydroxyproline assay. Despite demonstrable angiotensin II antagonism in vivo and a reduction in measures of acute lung injury, losartan therapy, at a dose shown to reduce renal and cardiac fibrosis in mice, failed to significantly ameliorate bleomycin-induced pulmonary fibrosis. In conclusion, these data suggest that the pulmonary fibrotic disease process in vivo is not solely dependent on angiotensin II activity and the potential for angiotensin II receptor blockers as a therapeutic strategy in patients with pulmonary fibrosis may be limited.

Angiotensin II Type 1 Receptor Blockers↗
PubMedDate not supplied

Mediastinal lymphadenopathy in pulmonary fibrosis: correlation with disease severity.

OBJECTIVE: To evaluate the relationship between mediastinal lymph node enlargement and disease severity score in patients with pulmonary fibrosis. MATERIALS AND METHODS: A retrospective study included 30 patients with pulmonary fibrosis: idiopathic pulmonary fibrosis (n = 25), usual interstitial pneumonia (UIP) associated with collagen vascular disease (n = 4), and UIP associated with hepatitis C (n = 1). Disease severity was determined by a computed tomography (CT) scoring system. Each patient's lobe was scored by two radiologists on a scale of 0-5 for both ground glass opacity (GGO) and fibrosis. The presence, number, and sites of enlarged nodes (short axis > or = 10 mm) were assessed. CT severity scores were compared with total number of enlarged lymph nodes (L/Ns) and short axis diameter of the largest L/N (LLN). According to each severity score, patients were divided into two groups: the GGO-predominant group (n = 10) and the fibrosis-predominant group (n = 20). Total numbers of enlarged L/Ns and short axis diameter of LLN were compared in each group. RESULTS: Enlarged mediastinal L/Ns were present in 86%. Total severity score, GGO score, and fibrosis score strongly correlated with total number of enlarged L/Ns (p<0.05). Total severity score and GGO score correlated well with short axis diameter of LLN; however, the fibrosis score did not correlate with the short axis diameter of LLN. In respect to total number of enlarged L/Ns, the difference between the GGO group and fibrosis group was not apparent. In respect to the short axis diameter of LLN, the GGO group LLN was larger in diameter than the fibrosis group LLN (p<0.05). CONCLUSION: The greater the severity score of pulmonary fibrosis, the larger the total number of enlarged L/Ns. Those patients with more GGO had larger lymph nodes.

Adult↗
PubMed1991

Immunogenetic prediction of pulmonary fibrosis in systemic sclerosis.

75 systemic sclerosis patients were independently tested for pulmonary fibrosis, autoantibodies, and MHC class II genes. 24 of 42 (57%) patients with pulmonary fibrosis had either HLA DR3/DRw52a or anti-Scl-70 vs 2 of 33 (6%) patients without pulmonary fibrosis. The presence of DR3/DRw52a or anti-Scl-70 gives a relative risk of 16.7 for the development of pulmonary fibrosis in a patient with scleroderma--a risk substantial enough to require careful monitoring of these patients and treatment at an early stage of disease.

Autoantibodies↗