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PubMed1996

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disorder characterized by inflammation, fibroblast proliferation, and accumulation of extracellular matrix proteins. Leukotrienes (LTs) are pro-inflammatory and pro-fibrogenic mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism. They are thought to play a role in a number of disease processes, but have received relatively little attention in investigations into the pathogenesis of IPF. In this study, we measured the levels of immunoreactive LTs B(4) and C(4) in homogenates of lung tissue obtained from patients with newly diagnosed, untreated IPF, as compared to levels measured in homogenates of uninvolved nonfibrotic lung tissue from patients undergoing resectional surgery for bronchogenic carcinoma. Compared to homogenates on nonfibrotic control lung, homogenates from IPF patients contained 15-fold more LTB(4) and 5-fold more LTC(4). IPF homogenate levels of LTB(4) were significantly correlated with histologic indices of both inflammation (r=0.861) and fibrosis (r=0.926). Activation of 5-LO is known from in vitro studies to be associated with localization of the enzyme at the nuclear membrane. Immunohistochemical staining for 5-LO protein in alveolar macrophages (AMs) demonstrated that such an "activated" localization pattern was significantly more frequent in IPF lung (19.2+/-3.3% of cells) than in control lung (9.3+/-0.9%); this localization pattern was rarely seen (3.2%) in sections from a truly normal transplant donor lung. Consistent with these data, AMs obtained from IPF patients by bronchoalveolar lavage, purified by adherence, and cultured in the absence of a stimulus for 16 h elaborated significantly greater amounts of LTB(4) and LTC(4) than did control AMs obtained from normal volunteers. These data indicate that the 5-LO pathway is constitutively activated in the lungs of patients with IPF, and the AM represents at least one cellular source of LT overproduction in this disorder. We speculate that LTs participate in the pathogenesis of IPF, and their overproduction in this disorder may be amenable to specific pharmacotherapy.

Adult↗

PubMed2005

Diagnosis: to biopsy or not to biopsy: assessing the role of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disorder that is associated with a poorer prognosis than subacute idiopathic interstitial pneumonias (IIPs). IPF can be differentiated from other IIPs on the basis of its histologic pattern of usual interstitial pneumonia (UIP). Although a surgical lung biopsy specimen showing a UIP pattern is required for the definitive diagnosis of IPF, clinical criteria can be used in the absence of a lung biopsy specimen to make a likely diagnosis of IPF. The predictive value of these criteria largely depends on the expertise of the clinician and radiologist, but considerable interobserver variability exists even when evaluations are performed by experts in the field. Moreover, these criteria lead to misdiagnosis in about 25 to 35% of cases. Interobserver variability is reduced and diagnostic accuracy is improved in cases in which a diagnosis is made with a high degree of confidence. Diagnostic accuracy is also higher when the diagnosis is made by a core group of experts rather than by a referring center. The decision on whether or not to perform a surgical lung biopsy is difficult. It is clearly indicated in cases in which clinical or radiologic findings are atypical or when the diagnosis is made with a low degree of certainty.

Biopsy↗

PubMed2006

Discoidin domain receptor 1 contributes to the survival of lung fibroblast in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-kappaB activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro DDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DDR1. The DDR1 expression level was significantly higher in fibroblasts from IPF patients, and the predominant isoform was DDR1b. In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-kappaB nuclear translocation. Suppression of DDR1 expression in fibroblasts by siRNA abolished these effects, and an NF-kappaB inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DDR1 up-regulation may occur in other fibroproliferative lung diseases as well.

Actins↗

PubMed1990

Upregulation of platelet-derived growth factor-A and -B gene expression in alveolar macrophages of individuals with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by accumulation of alveolar macrophages spontaneously releasing exaggerated amounts of the potent mesenchymal cell growth factor platelet-derived growth factor (PDGF). To evaluate the relative contribution of the two PDGF genes to this process, PDGF-A and -B gene transcription rates and mRNA levels were examined in normal and IPF alveolar macrophages. While normal alveolar macrophages constitutively transcribe both PDGF-A and PDGF-B genes, LPS stimulation increases the transcription of both genes more than threefold. Importantly, IPF alveolar macrophages spontaneously transcribe both genes at a rate similar to that observed for normal macrophages after in vitro stimulation. Consistent with the transcription data, normal macrophages contain mRNA for both PDGF-A and -B, but PDGF-B mRNA is 10-fold more abundant. Strikingly, in IPF, both PDGF-A and -B mRNA levels were markedly increased, with persistence of the 10-fold dominance of PDGF-B mRNA. Thus, the exaggerated release of PDGF by IPF alveolar macrophages is likely modulated by upregulated PDGF gene transcription rates and concomitantly increased mRNA levels and the persistent 10-fold excess of B greater than A PDGF mRNA suggests that the PDGF released by alveolar macrophages is likely mostly of the potent B-chain homodimeric form.

Blotting, Northern↗

PubMed2000

Frequent genetic alterations at the microsatellite level in cytologic sputum samples of patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology associated with DNA damage and malignancy. Bronchogenic carcinoma is the cause of death in 10% to 13% of IPF patients. Microsatellite instability (MSI) and loss of heterozygosity (LOH) are frequently detected in cancers. If these genetic alterations could be observed in IPF, they might explain the higher relative risk of lung cancer in this disease. We investigated the incidence of MSI and LOH in sputum cytologic specimens from 26 IPF patients and 26 healthy, matched subjects, using 10 highly polymorphic microsatellite markers. The electrophoretic pattern of each specimen was compared with that of corresponding peripheral blood. Thirteen (50%) patients showed genetic alterations, consisting either of MSI or LOH. Five (19%) patients exhibited MSI and 10 (39%) exhibited LOH in at least one microsatellite marker. Three (12%) patients showed LOH in more than one marker. None of the healthy subjects exhibited genetic alterations in the studied markers. No correlation was found between the detected genetic alterations and age, disease duration, blood gases, or spirometric parameters of the patients. Our findings suggest that the genetic alterations that we studied are frequent in IPF, are apparently unrelated to the severity of the disease, and may be related to tumorigenesis.

Aged↗

PubMed1997

Increased production of the potent oxidant peroxynitrite in the lungs of patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by alveolar inflammation, progressive proliferation of septal cells, increased production of septal matrix, and loss of lung architecture. The process of cellular injury in lung fibrosis is thought to be mediated by oxygen radicals produced by infiltrating inflammatory cells. Peroxynitrite is a potent oxidant produced by the rapid reaction of nitric oxide (NO) and superoxide. We investigated the production of nitrotyrosine, a byproduct of protein nitration by peroxynitrite, and the expression of the enzymes responsible for generating NO, in lungs of patients with IPF and compared them with lungs of normal control subjects. We used immunohistochemistry, histochemistry, and in situ hybridization to study the production of nitrotyrosine and the expression of inducible (iNOS) and constitutive endothelial (eNOS) nitric oxide synthases in 48 lungs of patients with different stages of IPF and 21 normal lungs. In lungs of control subjects, there was little expression of iNOS and nitrotyrosine in the airway epithelium and alveolar macrophages, and abundant expression of eNOS in the airway epithelium and vascular endothelium. By contrast, in lungs of patients with IPF, strong expression of nitrotyrosine and NOS was seen in macrophages, neutrophils, and alveolar epithelium. A significant increase in the expression of these molecules was only seen in lungs of patients with the early to intermediate stage of the disease. The active stage of IPF is associated with increased inflammatory and alveolar expression of nitrotyrosine and NOS. Increased production of NO and peroxynitrite may be responsible for the oxidative damage seen in this disease.

Endothelium, Vascular↗

PubMed1998

Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a generally fatal disorder with a reported median survival of 3 to 6 yr. This has been based on relatively few studies with diagnoses inconsistently confirmed by adequate lung biopsy. Retrospective analysis of 104 patients with IPF who had open lung biopsy (OLB) at Mayo Medical Center from 1976 to 1985 was performed to establish the overall survival rate, the spectrum of histopathological subgroups and their associated prognostic significance. The study group consisted of 54 men and 50 women with a median age of 63 yr. Median survival was 3.8 yr after diagnosis by OLB with an estimated 10 yr survival of 27%. Current histopathologic review showed a heterogeneous group including usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia/fibrosis (NSIP), acute interstitial pneumonia (AIP), bronchiolitis, bronchiolitis obliterans organizing pneumonia (BOOP), and others. Median survival of the UIP group was 2.8 yr which is significantly worse (p < 0.001) than for other subgroups of chronic interstitial pneumonias. IPF includes several histopathologic subgroups with significantly different survival rates. Patients with UIP have worse survival than patients with other types of idiopathic chronic interstitial pneumonias including NSIP. Accurate histopathologic classification is essential for prognostication in patients with IPF.

Adult↗

PubMed2003

Analysis of an IL-10 polymorphism in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic disorder of the lung parenchyma. We have demonstrated changes in IL-10 protein production by alveolar macrophages (AMs) from patients with IPF, which we hypothesise could be because of an IL-10 gene polymorphism. We have screened the coding sequence and 3' untranslated region of IL-10 for polymorphisms using single-standard conformational polymorphism analysis. A novel polymorphism was identified resulting in a G to A substitution of +43 nucleotides from the start codon changing glycine to arginine at amino acid 15 of the signal peptide sequence. We have introduced the signal peptide mutation into the IL-10 gene and compared secretion of the mutant and wild-type forms after transient transfection of COS-7 cells. Our studies showed that the signal peptide mutation did not have a significant effect on secretion at 24 h post-transfection (P=0.4529 by Mann-Whitney test). However, by 48 h there are significantly lower levels of mutant IL-10 (P=0.0515). There were no differences in the level of cell-associated IL-10 at either 24 or 48 h (P=0.9296 and 0.4268). We suggest that the mutation could affect the efficiency of protein translocation and signal peptide cleavage resulting in lower levels of IL-10 protein secretion.

Adult↗

PubMed2006

Tissue inhibitor of metalloproteinase-3 is up-regulated by transforming growth factor-beta1 in vitro and expressed in fibroblastic foci in vivo in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by fibroblast expansion and extracellular matrix accumulation. However, the mechanisms involved in matrix remodeling have not been elucidated. In this study, the authors aimed to evaluate the expression of the tissue inhibitors of matrix metalloproteinases (TIMPs) in human fibroblasts and whole tissues from IPF and normal lungs. They also determined the role of mitogen-activated protein kinase (MAPK) in TIMP3 expression. TIMP1, TIMP2, and TIMP3 were highly expressed in lung fibroblasts. Transforming growth factor (TGF)-beta1, a profibrotic mediator, induced strong up-regulation of TIMP3 at the mRNA and protein levels. The authors examined whether the MAPK pathway was involved in TGF-beta1-induced TIMP3 expression. TGF-beta1 induced the phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2. Biochemical blockade of p38 by SB203580, but not of the ERK MAPK pathway, inhibited the effect of this factor. The effect was also blocked by the tyrosine kinase inhibitor genistein and by antagonizing TGF-beta1 receptor type I (activin-linked kinase [ALK5]). In IPF tissues TIMP3 gene expression was significantly increased and the protein was localized to fibroblastic foci and extracellular matrix. Our findings suggest that TGF-beta1-induced TIMP3 may be an important mediator in lung fibrogenesis.

Cells, Cultured↗

PubMed1995

Expression of cell adhesion molecules in the lungs of patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory disorder restricted to the lungs. Leukocyte entry into the area of inflammation is regulated, at least partly, by endothelial expression of leukocyte-selective cell adhesion molecules (CAMs). To investigate the relevance of these CAMs to the accumulation of leukocytes in IPF, we examined the expression of E-selectin (endothelial leukocyte adhesion molecule-1; ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) by immunohistochemistry in lung tissue from nine patients with IPF and five nonsmoking normal subjects. The results demonstrated that in normal lungs, ICAM-1 was weakly expressed on endothelial cells, but neither E-selectin nor VCAM-1 was detected. In the lungs of patients with IPF, E-selectin expression on endothelial cells was restricted to honeycombing regions. Endothelial expression of ICAM-1 was increased throughout the tissue, but VCAM-1 was not detected in IPF. The distribution of leukocytes in lungs with IPF consisted of mostly lymphocyte accumulation in the interstitium and neutrophil accumulation within the airspaces of honeycomb regions. These results suggest that E-selectin may play a role in the recruitment of neutrophils in regions of honeycombing and that ICAM-1 may play a role in lymphocyte recruitment into the interstitium in addition to contributing to neutrophil recruitment in regions of honeycombing in patients with IPF.

Aged↗

PubMed1999

The detection of Epstein-Barr virus DNA in lung tissue from patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a clinical syndrome in which the precipitating factors are unclear. An association between Epstein-Barr Virus (EBV) and IPF had previously been suggested using serology and immunohistochemistry. This study sought confirmation of the presence of EBV DNA in the lung tissue of patients with IPF. Lung tissue obtained surgically from 27 patients with IPF and 28 control subjects was investigated for the presence of EBV by immunohistochemistry and polymerase chain reaction (PCR) analysis. Immunohistochemistry used antibodies specific for EBV lytic cycle antigens (gp340/220 and VCA). Nested PCR analysis used oligonucleotide primers specific for EBV and was sensitive to one copy of EBV DNA. Twelve of the 27 patients with IPF (44%) and three of the 28 control subjects (10%) were EBV positive by immunohistochemistry (p = 0.005). Thirteen of the patients with IPF (48%) and four of the control subjects (14%) were EBV positive by PCR (p = 0.007). Eleven of the patients with IPF (41%) and none of the control subjects were EBV positive by both immunohistochemistry and PCR (p = < 0.001). These data further suggest an association between EBV and IPF. In addition it defines a novel method for detecting EBV in lung tissue. EBV may be involved in the pathogenesis of the disease; however, further studies are required to establish a causal relationship.

Adult↗

PubMed2005

Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder without an effective therapy to date. In a double-blind, randomized, placebo-controlled trial, 107 patients were prospectively evaluated for efficacy of a novel compound, pirfenidone. The difference in the change in the lowest oxygen saturation by pulse oximetry (SpO2) during a 6-minute exercise test, the primary endpoint, from baseline to 6 months was not significant between the two groups (p = 0.0722). In a prespecified subset of patients who maintained a SpO2 greater than 80% during a 6-minute exercise test at baseline, the lowest SpO2 improved during a 6-minute exercise test in the pirfenidone group at 6 and 9 months (p = 0.0069 and 0.0305, respectively). Positive treatment effect was demonstrated in secondary endpoints: (1) change in VC measurements at 9 months (p = 0.0366) and (2) episodes of acute exacerbation of IPF occurring exclusively in the placebo group during the 9 months (p = 0.0031). Significant adverse events were associated with pirfenidone; however, adherence to treatment regimen was similar between pirfenidone and placebo groups. In conclusion, treatment with pirfenidone improved VC and prevented acute exacerbation of IPF during the 9 months of follow-up. Future long-term studies are needed to clarify the overall safety and efficacy of pirfenidone in IPF.

Aged↗

PubMed2006

Bone morphogenetic protein-4 inhibitor gremlin is overexpressed in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), ie, usual interstitial pneumonia in histopathology, is a disease characterized by tissue destruction and active areas of fibroproliferation in the lung. Gremlin (Drm), a member of the cysteine knot family of bone morphogenetic protein (BMP) inhibitors, functions to antagonize BMP-4-mediated signals during lung development. We describe here consistent overexpression of gremlin in the lung interstitium of IPF patients. Quantitative real-time reverse transcriptase-polymerase chain reaction analyses revealed considerably higher levels of gremlin mRNA in lung biopsies from IPF patients, the highest level being 35-fold higher compared to controls. Lung fibroblasts isolated from IPF patients also expressed elevated levels of gremlin, which was associated with impaired responsiveness to endogenous and exogenous BMP-4. Transforming growth factor-beta-induced epithelial-to-mesenchymal transition of A549 lung epithelial cells in culture was also associated with induction of gremlin mRNA expression. In addition, A549 cells transfected to overexpress gremlin were more susceptible to transforming growth factor-beta-induced epithelial-to-mesenchymal transition. Gremlin-mediated inhibition of BMP-4 signaling pathways is likely to enhance the fibrotic response and reduce epithelial regeneration in the lung. The overexpression of this developmental gene in IPF may be a key event in the persistence of myofibroblasts in the lung interstitium and provides a potential target for therapeutic intervention.

Blotting, Northern↗

PubMed1988

Increased procollagen III aminoterminal peptide-related antigens and fibroblast growth signals in the lungs of patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by an increased density of inflammatory cells, fibroblasts, and collagen within the lung parenchyma. To gain insights into the mechanisms leading to the increased density of fibroblasts and altered collagen metabolism in the IPF lung, bronchoalveolar lavage fluid from normal subjects and patients with IPF or sarcoidosis was analyzed for (1) the presence of antigenic material related to the aminoterminal propeptide domain of type III procollagen, and (2) fibroblast growth-promoting activity in the extracellular milieu of the lower respiratory tract. Whereas bronchoalveolar lavage fluid (BALF) type III procollagen aminoterminal peptide-related antigen levels in 59 patients with sarcoidosis were similar to the levels of control subjects (p greater than 0.10), 31 patients with IPF had markedly increased levels (12-fold over controls; p less than 0.025, IPF versus controls; p less than 0.01, IPF versus sarcoidosis). Type III procollagen aminoterminal peptide-related antigen levels correlated with an increase in the ability of BALF to stimulate fibroblast proliferation (p less than 0.05). Furthermore, BALF from patients with IPF markedly stimulated human lung fibroblast proliferation in vitro (199% increase, p less than 0.01), whereas lavage fluid from patients with sarcoidosis and from control subjects did not. The enhanced fibroblast proliferation induced by IPF BALF occurred in the absence of serum and exogenous growth factors, suggesting that both competence- and progression-type growth factors were present in the lavage fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2001

Aberrations in the fragile histidine triad (FHIT) gene in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) seems to be closely associated with lung carcinogenesis. To identify the genetic characteristics of precancerous IPF lesions in the peripheral lung, we performed PCR-based microsatellite analysis with DNA extracted from microdissected tissues; fluorescent in situ hybridization (FISH) analysis of the fragile histidine triad (FHIT) gene and immunohistochemical analysis of Fhit protein expression in samples of metaplasias and bronchiolar epithelia obtained from patients with IPF. We used four microsatellite markers of the FHIT gene within or flanking the FHIT gene on chromosome 3p for loss of heterozygosity (LOH) analysis. LOH of the FHIT locus was frequently found among the lesions of metaplasias and bronchiolar epithelia in the patients with IPF [62 (52%) of 119 informative lesions]. Fifty-four (73%) of the 74 lesions of metaplasias and bronchiolar epithelia obtained from the IPF patients with lung carcinoma and 8 (17%) of the 46 samples obtained from the IPF patients without lung carcinoma showed LOH at the FHIT gene (P < 0.0001). We confirmed allelic loss in the metaplasias and bronchiolar epithelia of IPF by FISH analysis of the FHIT gene. Additionally, the level of Fhit protein expression in the metaplastic cells of IPF was frequently reduced. Our findings suggest that allelic loss of the FHIT gene may be involved in carcinogenesis in the peripheral lung of patients with IPF.

Acid Anhydride Hydrolases↗

PubMed1990

Oxygen radical production by alveolar inflammatory cells in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease characterized by the accumulation of alveolar macrophages (AMs) and neutrophils in the lower respiratory tract, parenchymal cell injury, and fibrosis of the alveolar structure. Reactive oxygen intermediates (ROI) are claimed to be a major cause of tissue damage in IPF; however, the source of ROI has not been unequivocally identified. AMs, as well as neutrophils, are capable of releasing these agents. The contributions of these possible sources are not known. To address this question, we evaluated the spontaneous and stimulated (PMA or zymosan) ROI release of total bronchoalveolar cells and isolated AMs in 14 patients with IPF by means of luminol-enhanced chemiluminescence. Bronchoalveolar lavage (BAL) cells from 17 individuals without any signs of inflammation served as controls. In comparison with the controls, the spontaneous as well as the stimulated ROI release of total BAL cells in IPF are markedly increased (20,763.9 +/- 5,079.3 versus 2,509.5 +/- 300.6 counts/10 s/2.10(5) cells, spontaneously, IPF versus control; 106,819.3 +/- 33,802.8 versus 8,919 +/- 1,357.9 PMA induced; 41,597.1 +/- 8,442.6 versus 6,223.8 +/- 1,025.1 zymosan induced, p less than 0.001). Measurement of the ROI release of purified AMs revealed that these cells produce the bulk part of ROI released by BAL cells (84%). In spite of the fact that, on a per cell basis, the ROI release of neutrophils is 1.7-fold of that of AMs, there is no correlation between the ROI production of total BAL cells and the percentage of neutrophils in BAL, demonstrating a minor role of these cells in the generation of the total ROI burden in IPF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Determinants of progression in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive form of lung disease with a median survival of less than 5 yr. To address the progressive nature of this disease process, we investigated the determinants of decrements in lung function in patients with IPF. We prospectively evaluated 39 subjects with IPF. Our study subjects were followed for an average of 2 yr (range, 49 to 1,883 days) and lung function was measured on at least two separate occasions (mean = 9.1 separate tests) during the follow-up period. Since IPF is characterized by reduced lung volume and abnormal gas exchange, our analysis focused on the determinants of total lung capacity (TLC) and diffusing capacity of carbon monoxide (DLCO) during the period of observation. Although, on average, there was a 5.3% increase in the TLC and a 9.8% increase in DLCO between the first and last measure of lung function, 25% of the study population experienced a decline in the TLC and 28% of the study population experienced a decline in the DLCO. Decrements in TLC were independently associated with severe dyspnea (p = 0.01) and treatment with cyclophosphamide (p = 0.03). Decrements in DLCO were significantly and independently associated with more pack-years of cigarette smoking (p = 0.02), moderate (p = 0.03) or severe (p = 0.02) dyspnea, and treatment with cyclophosphamide (p = 0.0002). These findings indicate that several clinical characteristics are independently associated with subsequent declines in TLC and DLCO in patients with IPF.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchoalveolar Lavage Fluid↗

PubMed2000

Neutrophil inflammation and activation in bronchiectasis: comparison with pneumonia and idiopathic pulmonary fibrosis.

BACKGROUND: Pulmonary inflammation in bronchiectasis, pneumonia and idiopathic pulmonary fibrosis (IPF) is dominated by neutrophils. Pathophysiologic differences are seen in the degree of airway and tissue destruction. Neutrophil activation and neutrophil proteolytic activity might differ between bronchiectasis, pneumonia and IPF. OBJECTIVE: The aim of this study was to determine whether levels of inflammatory and protective markers in bronchoalveolar lavage (BAL) differed among cases of bronchiectasis, pneumonia and IPF. METHODS: We studied 11 bronchiectasis patients (group 1), 30 pneumonia patients (group 2), 15 IPF patients (group 3) and 12 healthy volunteers (group 4). In the bronchoalveolar lavage fluid, concentrations of alpha(1)-proteinase inhibitor, myeloperoxidase (MPO) and elastase-alpha(1)PI complex were determined using immunoluminometric assays. Elastase inhibition capacity (EIC) and elastase activity were determined using a colorimetric assay. RESULTS: No EIC, but free elastase activity, was found in 82% of group 1, 20% of group 2, 20% of group 3 and 0% of group 4. Median MPO concentration was highest in group 1: 7,951 ng/ml (16th-84th percentile [16-84%]: 256-36,342) vs. 692 ng/ml (106-2,279; group 2), 332 ng/ml (98-1,657; group 3), and 0.12 ng/ml (0.08-0.26; group 4). Bronchiectasis patients with bronchial Pseudomonas infection showed higher amounts of neutrophils (p < 0.01) and higher elastase activity (p < 0.05) than patients with sterile lavage. CONCLUSION: Bronchiectasis patients show a severe imbalance between neutrophil activity and protective molecules leading to possible lung destruction. Chronic Pseudomonas infection might trigger neutrophil activation. Future research and treatment strategies should focus on increased bacterial clearance and inhibition of neutrophil toxicity.

Adult↗