interleukin-8 and Pulmonary-Fibrosis

The usefulness of selected serum biomarkers (KL-6, SP-A, SP-D, IL-8, MCP-1, CYFRA-21) in diagnosis, monitoring and prognosis prediction of idiopathic pulmonary fibrosis is discussed in this paper.

Topics: Antigens, Neoplasm; Biomarkers; Carrier Proteins; Chemokine CCL2; Humans; Interleukin-8; Keratin-19; Keratins; Mucin-1; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein D

Topics: Humans; Immunity, Innate; Interleukin-8; Leukotriene B4; Macrophages, Alveolar; Pneumonia; Pulmonary Fibrosis

A variety of factors have been identified that regulate angiogenesis, including the CXC chemokine family. The CXC chemokines are a unique family of cytokines for their ability to behave in a disparate manner in the regulation of angiogenesis. CXC chemokines have four highly conserved cysteine amino acid residues, with the first two cysteine amino acid residues separated by one non-conserved amino acid residue (i.e., CXC). A second structural domain within this family determines their angiogenic potential. The NH2 terminus of the majority of the CXC chemokines contains three amino acid residues (Glu-Leu-Arg: the ELR motif), which precedes the first cysteine amino acid residue of the primary structure of these cytokines. Members that contain the ELR motif (ELR+) are potent promoters of angiogenesis. In contrast, members that are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis. This difference in angiogenic activity may impact on the pathogenesis of a variety of disorders.

Topics: Amino Acid Motifs; Angiogenesis Inhibitors; Animals; Arthritis, Rheumatoid; Chemokine CXCL10; Chemokines, CXC; Chronic Disease; Fibrosis; Humans; Inflammation; Interleukin-8; Mice; Mice, Nude; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Pulmonary Fibrosis; Receptors, Chemokine; Structure-Activity Relationship

Pulmonary fibrosis is a frequent and serious complication of scleroderma whose pathophysiology remains poorly understood. The alveolar structures are infiltrated by activated chronic inflammatory cells, alveolar macrophages and polymorphonuclear neutrophils in particular and these could play a determining role. We have studied the state of activation of alveolar macrophages and monocytes circulating in these patients who presented with scleroderma and interstitial pulmonary involvement and also in healthy subjects. The neutrophil alveolitis observed in the patients is accompanied by a raised level of interleukin-8 secretion by the alveolar macrophages compared to the healthy subjects. Interleukin-8 is an important chemotactic molecule for polymorphonuclear neutrophils in the lung. The neutrophil alveolitis is accompanied by a breakdown in the equilibrium of elastase-antielastase which could participate in the development of alveolar lesions leading to fibrosis. In addition to the activation of macrophages, there is an activation of monocytes marked by the increase in secretion of interleukin-6 and interleukin-8 in vitro during the progression of the disease of scleroderma. Thus, alveolar inflammation is integrated with the overall systemic inflammation whose causes remain unknown.

Topics: Case-Control Studies; Humans; Interleukin-6; Interleukin-8; Macrophage Activation; Macrophages, Alveolar; Monocytes; Neutrophil Activation; Neutrophils; Pulmonary Fibrosis; Scleroderma, Systemic

Fibrosis is a pathological process characterized by the replacement of normal tissue by mesenchymal cells and the extracellular matrix produced by these cells. The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in the area of derangement. The same sequence of events occurs in wound healing with normal granulation tissue and scar formation, but, while normal scar formation is very localized and transient, in contrast, in fibrosis, the repair process is exaggerated and usually widespread and can be chronic. Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair. The evaluation of three human fibrotic lung diseases, two diffuse [idiopathic pulmonary fibrosis (IPF), and the adult respiratory distress syndrome (ARDS)], and one focal (tumor stroma in lung cancer), has shown that several cytokines participate to the local injury and inflammatory reaction [interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha)], while other cytokines are involved in tissue repair and fibrosis [platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)]. A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches.

Topics: Cytokines; Humans; Interleukin-1; Interleukin-8; Molecular Weight; Platelet-Derived Growth Factor; Pulmonary Fibrosis; Respiratory Distress Syndrome; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wound Healing

The recruitment of leukocyte populations to an area of inflammation is one of the most fundamental processes of immune reactivity, yet a number of the mechanisms which are important to this process are not clearly understood. Investigations directed at understanding the mechanisms of leukocyte elicitation have centered around classical chemotactic factors such as C5a and fMLP, however, these known agents have demonstrated little specificity for recruiting particular leukocyte populations. Recent advances in this field have been made with the discovery of a novel supergene family of chemotactic cytokines or chemokines. These cytokines are important as they possess a high degree of specificity for the recruitment of specific subpopulations of leukocytes.

Topics: Adult; Chemotaxis, Leukocyte; Cytokines; Humans; Inflammation; Interleukin-8; Lung Diseases; Multigene Family; Pulmonary Fibrosis; Respiratory Distress Syndrome

We previously reported that the combination of mean lung dose (MLD) and inflammatory cytokines interleukin-8 (IL-8) and transforming growth factor-β1 (TGF-β1) may provide a more accurate model for radiation-induced lung toxicity (RILT) prediction in 58 patients with non-small cell lung cancer (NSCLC). This study is to validate the previous findings with new patients and to explore new models with more cytokines.. One hundred forty-two patients with stage I-III NSCLC treated with definitive radiation therapy (RT) from prospective studies were included. Sixty-five new patients were used to validate previous findings, and all 142 patients were used to explore new models. Thirty inflammatory cytokines were measured in plasma samples before RT and 2 weeks and 4 weeks during RT (pre, 2w, 4w). Grade ≥2 RILT was defined as grade 2, and higher radiation pneumonitis or symptomatic pulmonary fibrosis was the primary endpoint. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the receiver operating characteristic curves was used for model assessment.. Sixteen of 65 patients (24.6%) experienced RILT2. Lower pre IL-8 and higher TGF-β1 2w/pre ratio were associated with higher risk of RILT2. The AUC increased to 0.73 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.61 by MLD alone to predict RILT. In all 142 patients, 29 patients (20.4%) experienced grade ≥2 RILT. Among the 30 cytokines measured, only IL-8 and TGF-β1 were significantly associated with the risk of RILT2. MLD, pre IL-8 level, and TGF-β1 2w/pre ratio were included in the final predictive model. The AUC increased to 0.76 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.62 by MLD alone.. We validated that a combination of mean lung dose, pre IL-8 level, and TGF-β1 2w/pre ratio provided a more accurate model to predict the risk of RILT2 compared with MLD alone.

Topics: Aged; Area Under Curve; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cytokines; Female; Humans; Interleukin-8; Logistic Models; Lung Neoplasms; Male; Middle Aged; Pulmonary Fibrosis; Radiation Pneumonitis; Radiotherapy, Conformal; Transforming Growth Factor beta1

Little is known about the effects of long-term nasal low-flow oxygen (NLFO) on mucus and symptoms and how this variable is affected by dry or cold humidified gas. The aim of this study was to investigate the effects of dry-NLFO and cold bubble humidified-NLFO on nasal mucociliary clearance (MCC), mucus properties, inflammation, and symptoms in subjects with chronic hypoxemia requiring long-term domiciliary oxygen therapy.. Eighteen subjects (mean age, 68 years; 7 male; 66% with COPD) initiating NLFO were randomized to receive dry-NLFO (n = 10) or humidified-NLFO (n = 8). Subjects were assessed at baseline, 12 h, 7 days, 30 days, 12 months, and 24 months by measuring nasal MCC using the saccharin transit test, mucus contact angle (surface tension), inflammation (cells and cytokine concentration in nasal lavage), and symptoms according to the Sino-Nasal Outcome Test-20.. Nasal MCC decreased significantly (40% longer saccharin transit times) and similarly in both groups over the study period. There was a significant association between impaired nasal MCC and decline in lung function. Nasal lavage revealed an increased proportion of macrophages, interleukin-8, and epidermal growth factor concentrations with decreased interleukin-10 during the study. No changes in the proportion of ciliated cells or contact angle were observed. Coughing and sleep symptoms decreased similarly in both groups. There were no outcome differences comparing dry vs cold bubble humidified NLFO.. In subjects receiving chronic NLFO, cold bubble humidification does not adequately humidify inspired oxygen to prevent deterioration of MCC, mucus hydration, and pulmonary function. The unheated bubble humidification performed no better than no humidification.. ClinicalTrials.gov; No.: NCT02515786; URL: www.clinicaltrials.gov.

Topics: Aged; Aged, 80 and over; Bronchiectasis; Cough; Cytokines; Disease Progression; Epidermal Growth Factor; Female; Humans; Humidifiers; Humidity; Hypertension, Pulmonary; Interleukin-10; Interleukin-8; Macrophages; Male; Middle Aged; Mucociliary Clearance; Mucus; Nasal Lavage Fluid; Oxygen Inhalation Therapy; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Respiratory Function Tests; Surface Tension

To observe the effect of ginkgo extract on pulmonary interstitial fibrosis.. Forty-five patients with pulmonary interstitial fibrosis were randomly divided into two groups, the treated group (n = 30) received ginkgo biloba extract 1 g, three times a day; the control group received prednisone 30 mg, once a day, the therapeutic course for both groups was 3 months. Changes of clinical symptoms, pulmonary function, arterial partial pressure of oxygen, computerized tomography (CT), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha(TNF-alpha) in the two groups were observed before and after treatment.. The efficacy of treatment in the two groups showed insignificant difference, clinical symptoms, pulmonary function, arterial partial pressure of oxygen were improved after treatment (P < 0.05), and the levels of IL-6, IL-8 and TNF-alpha significantly decreased after treatment as compared with those before treatment in the two groups. The occurrence of pulmonary infection was less in the treated group than that in the control group (P <0.05).. Ginkgo is effective in treating pulmonary interstitial fibrosis.

Topics: Aged; Drugs, Chinese Herbal; Female; Ginkgo biloba; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Phytotherapy; Pulmonary Fibrosis; Tumor Necrosis Factor-alpha

Extracellular glutathione deficiency and exaggerated oxidative stress may contribute to the pathogenesis of fibrosing alveolitis (FA). High-dose N-acetylcysteine (NAC) supplementation partially reverses extracellular glutathione depletion and oxidative damage, but effects on intracellular glutathione are unknown. Intracellular total glutathione (GSHt) and activation of bronchoalveolar lavage cells (BAC) obtained from 18 FA patients (9 males, aged 52+/-2 yrs), before and after 12 weeks of oral NAC (600 mg t.i.d.), were assessed. Eight healthy nonsmokers (2 males, aged 36+/-6 yrs) served as a control group. Intracellular GSHt was decreased in FA (1.57+/-0.20 nmol 1x10(6) BAC(-1) versus 2.78+/-0.43 nmol x 10(6) BAC(-1)). After NAC treatment, the intracellular GSHt content increased (1.57+/-0.20 versus 1.87+/-0.19 nmol x 1 x 10(6) BAC(-1)). The spontaneous oxidative activity of BAC decreased after NAC treatment (2.7+/-0.8 versus 1.0+/-0.2 nmol x 1 x 10(6) BAC(-1) x h(-1)). Interleukin-8 concentration (82.1+/-31.5 versus 80.0+/-22.6 pg x mL bronchoalveolar fluid (BALF), nonsignificant (NS)) and myeloperoxidase activity (1.93+/-0.64 versus 1.55+/-0.47 mU x mL(-1) BALF, NS) did not change significantly, but were found to be inversely correlated to intracellular GSHt. In conclusion, high-dose N-acetylcysteine supplementation increases intracellular glutathione levels slightly. This increase is associated with a mild reduction of oxidative activity but not with a reduction of bronchoalveolar cell activation in these patients.

Topics: Acetylcysteine; Administration, Oral; Adult; Bronchoalveolar Lavage Fluid; Female; Free Radical Scavengers; Glutathione; Humans; Interleukin-8; Male; Middle Aged; Oxidative Stress; Peroxidase; Prospective Studies; Pulmonary Fibrosis

It has been reported that carbohydrate antigen sialyl Lewis (a) (CA19-9) levels are elevated in serum as well as in bronchoalveolar lavage fluid (BALF) of patients with pulmonary fibrosis. However, the biological significance of CA19-9 is unclear.. The purpose of the present study was to evaluate correlations between CA19-9 levels in BALF and several biochemical as well as clinical parameters in patients with pulmonary fibrosis. In addition, biological functions of CA19-9 were also examined.. We studied 24 patients with a diagnosis of pulmonary fibrosis: 16 with idiopathic pulmonary fibrosis (IPF) and 8 with pulmonary fibrosis associated with a collagen vascular disorder (PF-CVD). In BALF, carbohydrate antigens sialyl Lewis (a) (CA19-9), elastase: alpha(1)-proteinase inhibitor complex (E-PI), hepatocyte growth factor (HGF), LDH, IgG, IgA, albumin, and cell differentiation were measured. We also evaluated the effects of CA19-9 on neutrophil functions.. CA19-9/albumin levels in BALF significantly correlated with HGF/albumin, elastase/albumin, LDH/albumin, total number of alveolar macrophages, and total number of neutrophils. Purified CA19-9 had a chemotactic activity for neutrophils. In addition, neutrophil chemotactic activity to C5a, fMLP, and interleukin 8 was significantly stimulated after incubation with purified CA19-9. Furthermore, CA19-9 increased the expression of CD15s on neutrophils.. Our data demonstrated (i) CA19-9 in BALF correlated with other markers of inflammation in pulmonary fibrosis, and (ii) CA19-9 can modify neutrophil functions. These results suggest that CA19-9 may play a role in the process of lung injury in patients with pulmonary fibrosis.

Topics: Adult; Aged; Aged, 80 and over; alpha 1-Antitrypsin; Bronchoalveolar Lavage Fluid; CA-19-9 Antigen; Cell Differentiation; Chemotaxis, Leukocyte; Collagen Diseases; Complement C5a; Dose-Response Relationship, Drug; Female; Hepatocyte Growth Factor; Humans; Immunoglobulin A; Immunoglobulin G; Interleukin-8; L-Lactate Dehydrogenase; Leukocyte Elastase; Lung Diseases, Interstitial; Lymphocyte Activation; Macrophages, Alveolar; Male; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pulmonary Fibrosis; Serum Albumin

Qi deficiency and blood stasis are identified to be pathological factors of pulmonary fibrosis (PF) in traditional Chinese medicine (TCM) theory. Buyang Huanwu Decoction (BYHWD) is a traditional Chinese prescription ameliorating Qi deficiency and blood stasis.. The objective of this study was to investigate the anti-fibrosis effect of BYHWD and the potential molecular mechanism in rats.. Bleomycin was used to construct PF rat models. 27 PF rats were randomly divided into three groups based on treatments: model group (saline solution, n = 9), low-dose BYHWD group (3.5 g/kg, n = 9), and high-dose BYHWD group (14.0 g/kg, n = 9). Moreover, 9 normal rats were used as the blank group. The blood viscosity, coagulation indexes (APTT, TT, PT, and FIB), platelet-related parameters (PLT, PDW, MPV, PCT, and PLCR), platelet microparticles (PMPs), and inflammatory factors (IL-2, IL-10, IL-1β, IL-6, IL-8, IL-17, IFN-γ, TNF-α, PAC-1, HMGB1, NF-κB, and TF) were determined. The lung tissue samples of rats were observed after hematoxylin-eosin (HE) staining. The full component analysis of the BYHWD extract was performed using the ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. The signaling pathway included into the study was selected on the basis of bioinformatics analysis and the results of the phytochemical analysis. The expression levels of genes and proteins involved in the selected signaling pathway were detected.. Compared to the blank group, the whole blood viscosity, PLR, PDW, MPV, PCT, PLCR, PMPs, and the levels of IL-1β, IL-6, IL-8, IL-17, TNF-α, PAC-1, HMGB1, NF-κB, and TF were increased, while the levels of IL-2 and IL-10 were decreased in the model group. Both low-dose BYHWD and high-dose BYHWD reversed these PF-induced effects in spite of the fact that low-dose BYHWD had no significant effect on the level of NF-κB. In addition, BYHWD ameliorated PF-induced inflammation in the rat lung tissue. The phytochemical analysis of the BYHWD extract combined with the bioinformatics analysis suggested that the therapeutical effect of BYHWD on PF was related to the HMGB1/NF-κB pathway, which consisted of NF-κB, IKBKB, ICAM1, VCAM1, HMGB1, and TLR4. Both RT-qPCR and western blot analyses showed that PF induced increases in the expression levels of NF-κB, ICAM1, VCAM1, HMGB1, and TLR4, but a decrease in the expression level of IKBKB. Moreover, both low-dose BYHWD and high-dose BYHWD exerted the opposite effects, and recovered the expression levels of NF-κB, ICAM1, VCAM1, HMGB1, TLR4, and IKBKB, despite the fact that low-dose BYHWD had no effects on the mRNA expression levels of NF-κB or TLR4.. In summary, BYHWD alleviated PF-induced blood stasis, platelet activation, and inflammation in the rats. Our study suggested BYHWD had a therapeutic effect on PF and was a good alternative for the complementary therapy of PF, and the potential molecular mechanism was modulation of HMGB1/NF-κB signaling pathway, and it needs further study.

Topics: Animals; HMGB1 Protein; I-kappa B Kinase; Inflammation; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-6; Interleukin-8; NF-kappa B; Phytochemicals; Platelet Activation; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Following the humidifier disinfectant incident in Korea, polyhexamethylene guanidine phosphate (PHMG-P) has been used to establish lung fibrosis model animals. Herein, we investigated time-dependent changes after a single PHMG-P instillation (22 μg/lung) to identify the underlying pathogenesis and immune response involved in PHMG-P-induced lung fibrosis. Compared to control mice, body weight loss and blood biochemical and hematological changes were more remarkable in PHMG-P-instilled mice, an increase of total cell counts, infiltration of macrophages and neutrophils and necrotic cell death were also more notable in the lungs of PHMG-P-instilled mice. Pathological lesions were detected from Day 1 after exposure, deteriorating with time. In addition, secretion of anti-inflammatory mediators was rapidly inhibited from 6 h after exposure, and level of IL-24, a tissue repair-related cytokine, was up-regulated in the lungs of PHMG-P-instilled mice until Day 21 post-exposure. In vitro tests using BEAS-2B cells showed that PHMG-P disturbed structural and functional homeostasis of organelles and that intracellular ROS increase was considered as an important cause of PHMG-P-induced cell death. Additionally, co-culture with DNA, a polyanionic compound, clearly inhibited PHMG-P-induced necrosis, and increased IL-1β and TNF-α level and decreased IL-6 and IL-8 levels were observed following exposure to PHMG-P. Meanwhile, IL-8 secretion increased in cells exposed to PHMG-P-induced cell debris. Therefore, we suggest that necrotic cell debris may importantly contribute to the PHMG-P-induced inflammatory response and pathogenesis. In addition, PHMG-P-induced necrosis may be initiated by high affinity between PHMG-P and cell membrane.

Topics: Animals; Disinfectants; Guanidines; Interleukin-8; Mice; Necrosis; Pulmonary Fibrosis

Hypersensitivity pneumonitis (HP) is an interstitial lung disease, characterized by lung inflammation (non-fibrotic HP) that may often progresses to fibrosis (Fibrotic HP). The tumor necrosis factor (TNF) and its receptors (TNFR1 and TNFR2) can be found as soluble (sol) and transmembrane (tm) forms, playing pro-inflammatory functions but also has been related to immune regulatory functions. Bronchioalveolar lavage from fibrotic and non-fibrotic HP patients was obtained, and immune cells were characterized by flow cytometry, whereas soluble proteins were analyzed by ELISA. Compare to fibrotic HP patients, HP patients with non-fibrotic disease have accumulation of pro-inflammatory CD3+ myeloid cells, cell subpopulations that have decreased tmTNFR2 expression, and low frequency of regulatory-T cells. Whereas solTNF, solTNFR2, and IL-8 are increased. These findings suggest that the TNF pathway may explain, at least partially, the differences between both HP clinical forms. The evaluation of the TNF family molecules may help to develop new therapeutic approaches.

Topics: Alveolitis, Extrinsic Allergic; Bronchoalveolar Lavage Fluid; CD3 Complex; Female; Humans; Interleukin-8; Leukocytes; Lung; Male; Membrane Proteins; Middle Aged; Myeloid Cells; Pneumonia; Pulmonary Fibrosis; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

Pulmonary fibrosis is a disease in which lung tissues become fibrous and thereby causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract, secreting inflammatory cytokines, which subsequently leads to the development of pulmonary fibrosis. Aesculetin, a major component of the sancho tree and chicory, is known to biologically have antioxidant and anti-inflammatory effects. Human alveolar epithelial A549 cells were cultured for 24 h in conditioned media of THP-1 monocyte-derived macrophages (mCM) with 1-20 μM aesculetin. Micromolar aesculetin attenuated the cytotoxicity of mCM containing inflammatory tumor necrosis factor-α (TNF)-α and interleukin (IL)-8 as major cytokines. Aesculetin inhibited alveolar epithelial induction of the mesenchymal markers in mCM-exposed/IL-8-loaded A549 cells (≈47-51% inhibition), while epithelial markers were induced in aesculetin-treated cells subject to mCM/IL-8 (≈1.5-2.3-fold induction). Aesculetin added to mCM-stimulated A549 cells abrogated the collagen production and alveolar epithelial CXC-chemokine receptor 2 (CXCR2) induction. The production of matrix metalloproteinase (MMP) proteins in mCM-loaded A549 cells was reduced by aesculetin (≈52% reduction), in parallel with its increase in tissue inhibitor of metalloproteinases (TIMP) proteins (≈1.8-fold increase). In addition, aesculetin enhanced epithelial induction of tight junction proteins in mCM-/IL-8-exposed cells (≈2.3-2.5-fold induction). The inhalation of polyhexamethylene guanidine (PHMG) in mice accompanied neutrophil predominance in bronchoalveolar lavage fluid (BALF) and macrophage infiltration in alveoli, which was inhibited by orally administrating aesculetin to mice. Treating aesculetin to mice alleviated PHMG-induced IL-8-mediated subepithelial fibrosis and airway barrier disruption. Taken together, aesculetin may antagonize pulmonary fibrosis and alveolar epithelial barrier disruption stimulated by the infiltration of monocyte-derived macrophages, which is typical of PHMG toxicity, involving interaction of IL-8 and CXCR2. Aesculetin maybe a promising agent counteracting macrophage-mediated inflammation-associated pulmonary disorders.

Topics: A549 Cells; Alveolar Epithelial Cells; Animals; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Interleukin-8; Macrophages; Male; Mice, Inbred BALB C; Pulmonary Alveoli; Pulmonary Fibrosis; Signal Transduction; THP-1 Cells; Umbelliferones

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.

Topics: Animals; Apoptosis; Betacoronavirus; Caspase 8; Cell Line, Tumor; Chemokine CCL5; Chemokine CXCL10; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Disease Models, Animal; Epithelial Cells; Gene Expression Regulation; Humans; Interleukin-1beta; Interleukin-7; Interleukin-8; Lung; Mice; Mice, Transgenic; Necroptosis; Pandemics; Pneumonia, Viral; Pulmonary Fibrosis; SARS-CoV-2; Tumor Necrosis Factor-alpha

To investigate the ex vivo pro-inflammatory properties of classical and non-classical monocytes as well as myeloid dendritic cells (mDCs) in systemic sclerosis (SSc) patients.. Spontaneous production of CXCL10, CCL4, CXCL8 and IL-6 was intracellularly evaluated in classical, non-classical monocytes and Siglec-3-expressing mDCs from peripheral blood of SSc patients and healthy controls (HC) through flow cytometry. In addition, production of these cytokines was determined upon toll-like receptor (TLR) 4 plus Interferon-γ (IFN-γ) stimulation.. The frequency of non-classical monocytes spontaneously producing CXCL10 was increased in both limited (lcSSc) and diffuse cutaneous (dcSSC) subsets of SSc patients and CCL4 was augmented in dcSSc patients. The proportion of CCL4-producing mDCs was also elevated in dcSSc patients and the percentage of mDCS producing CXCL10 only in lcSSc patients. Upon stimulation, the frequency of non-classical monocytes expressing CXCL8 was increased in both patient groups and mDCs expressing CXCL8 only in lcSSc. Moreover, these parameters in unsupervised clustering analysis identify a subset of patients which are characterized by lung fibrosis and reduced pulmonary function.. These data point towards a role of activated non-classical monocytes and mDCs producing enhanced levels of proinflammatory cytokines in SSc, potentially contributing to lung fibrosis.

Topics: Adult; Aged; Chemokine CCL4; Chemokine CXCL10; Cytokines; Dendrites; Female; Humans; Interferons; Interleukin-8; Male; Middle Aged; Monocytes; Myeloid Cells; Pulmonary Fibrosis; Scleroderma, Systemic; Sialic Acid Binding Ig-like Lectin 1; Toll-Like Receptor 4

IL-8-dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible, pathological changes associated with elevated levels of IL-8 in the lung. To better understand the duality of IL-8-dependent host immunity to bacterial infection and lung pathology, we expressed human IL-8 transgenically in murine bronchial epithelium, and investigated the impact of overexpression on lung bacterial clearance, host immunity, and lung pathology and function. Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation and activation, and chemotaxis. There was enhanced protection against challenge with Pseudomonas aeruginosa, and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL-2, and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen OprF, indicating a regulatory T-cell phenotype. However, this enhanced bacterial immunity came at a high price of progressive lung remodeling, with increased inflammation, mucus hypersecretion, and fibrosis. There was increased expression of Ccl3 and reduced expression of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all of which resulted in impaired lung function with reduced compliance, increased resistance, and bronchial hyperreactivity as measured by whole-body plethysmography. These results show that IL-8 overexpression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodeling, and damaged tight junctions, leading to impaired lung function.

Topics: Animals; Chronic Disease; Humans; Immunity, Innate; Interleukin-8; Lung; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Pulmonary Fibrosis

Extracorporeal membrane oxygenation (ECMO) is a life-saving treatment for patients with severe refractory cardiorespiratory failure. Exposure to the ECMO circuit is thought to trigger/exacerbate inflammation. Determining whether inflammation is the result of the patients' underlying pathologies or the ECMO circuit is difficult. To discern how different insults contribute to the inflammatory response, we developed an ovine model of lung injury and ECMO to investigate the impact of smoke-induced lung injury and ECMO in isolation and cumulatively on pulmonary and circulating inflammatory cells, cytokines, and tissue remodeling. Sheep receiving either smoke-induced acute lung injury (S-ALI) or sham injury were placed on veno-venous (VV) ECMO lasting either 2 or 24 h, with controls receiving conventional ventilation only. Lung tissue, bronchoalveolar fluid, and plasma were analyzed by RT-PCR, immunohistochemical staining, and zymography to assess inflammatory cells, cytokines, and matrix metalloproteinases. Pulmonary compliance decreased in sheep with S-ALI placed on ECMO with increased numbers of infiltrating neutrophils, monocytes, and alveolar macrophages compared with controls. Infiltration of neutrophils was also observed with S-ALI alone. RT-PCR studies showed higher expression of matrix metalloproteinases 2 and 9 in S-ALI plus ECMO, whereas IL-6 was elevated at 2 h. Zymography revealed higher levels of matrix metalloproteinase 2. Circulating plasma levels of IL-6 were elevated 1-2 h after commencement of ECMO alone. These data show that the inflammatory response is enhanced when a host with preexisting pulmonary injury is placed on ECMO, with increased infiltration of neutrophils and macrophages, the release of inflammatory cytokines, and upregulation of matrix metalloproteinases.

Topics: Acute Lung Injury; Animals; Biomarkers; Bronchi; Bronchoalveolar Lavage; Compliance; Edema; Epithelial Cells; Extracorporeal Membrane Oxygenation; Immunohistochemistry; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukocyte Count; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Organ Size; Pneumonia; Pulmonary Fibrosis; Sheep; Smoking

We aimed to investigate the preventive and therapeutic effect of apocynin (APO) on bleomycin (BLC)-induced lung injury in rats. Rats were assigned into groups as follows: control group; APO group, 20 mg/kg APO was given intraperitoneal for 29 days; BLC-1 and BLC-2 groups, a single intratracheal injection of BLC (2.5 mg/kg); APO+BLC-preventive group, 20 mg/kg APO was administered 12 h before the intratracheal BLC injection and continued for 14 days; BLC+APO-treatment group, 20 mg/kg APO was given on the 14th day after the intratracheal BLC injection and continued to sacrifice. The BLC-1 group was sacrificed on the 14th day of BLC administration to validate BLC-induced lung inflammation and fibrosis on the 14th of study initiation. All other groups were sacrificed on the 29th day after BLC administration. The semiquantitative histopathological assessment, tissue levels of malondialdehyde (MDA), superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant capacity, total oxidant status (TOS), and oxidative stress index (OSI) were measured. An addition to the serum myeloperoxidase (MPO), the cell count and cytokines (IL-1β, IL-6, and IL-8) of bronchoalveolar lavage (BAL) fluid were assayed. BLC-provoked histological changes were significantly detected compared to the control group. APO restored these histological damages in different quantity in the treatment and prevention groups. BLC caused a significant decrease in GSH, CAT, and GPX, which were accompanied with significantly the increased MDA, TOS levels, and OSI in the lung tissue concomitant with increased levels of the cellular account and proinflammatory cytokines in the BAL fluid. Otherwise, APO administration, both before and after BLC, reversed all biochemical markers and cytokine as well as histopathological changes induced by BLC. Interestingly, APO treatment reversed MPO activity in serum increased by BLC. In this study, both protective and therapeutic effects of APO against BLC-induced lung fibrosis were demonstrated for the first time.

Topics: Acetophenones; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Bleomycin; Bronchoalveolar Lavage Fluid; Catalase; Disease Models, Animal; Female; Glutathione; Glutathione Peroxidase; Interleukin-1beta; Interleukin-6; Interleukin-8; Lung; Lung Injury; Malondialdehyde; Oxidative Stress; Peroxidase; Pulmonary Fibrosis; Rats; Rats, Wistar; Superoxide Dismutase

Coal workers' pneumoconiosis (CWP) is characterized as a chronic inflammation of the lung associated with activation of macrophages and endothelial cells in the lung. The aim of the present study was to compare the levels of serum interleukin-8 (IL-8), macrophage inflammatory protein-1α (MIP-α), and intercellular adhesion molecule-1 (ICAM-1) as biomarkers for progressive massive fibrosis (PMF) in 106 subjects (27 non-CWP and 79 CWP patients). The levels of serum IL-8 (P<0.001) and ICAM-1 (P=0.001) of subjects with PMF were higher than those of non-CWP subjects. The IL-8 levels of PMF subjects were also higher than those of simple CWP subjects (P=0.003). Among the subjects without PMF, IL-8 levels in the subjects with International Labour Organization (ILO) category II or III were higher than those in the subjects with ILO category 0 (P=0.006) and with category I (P=0.026). These results suggest that high serum levels of IL-8 and ICAM-1, which are important as neutrophil attractants and adhesion molecules, are associated with PMF.

Topics: Aged; Anthracosis; Biomarkers; Chemokine CCL3; Coal Mining; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Lung; Male; Middle Aged; Occupational Diseases; Pulmonary Fibrosis

The purpose of this study is to evaluate the relationship between the concentration of interleukin-8 (IL-8) in exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) with the disease activity score and pulmonary function of systemic lupus erythematosus (SLE) patients with and without pulmonary fibrosis. Thirty-four SLE patients and 31 healthy controls were enrolled and evaluated using high-resolution computed tomography (HRCT), pulmonary function tests, systemic lupus activity measure (SLAM), assessing BALF and EBC. IL-8 levels in BALF and EBC samples were measured with an enzyme-immunosorbent assay kit. The mean (±SEM) IL-8 concentrations in BALF and EBC were higher in SLE patients compared to healthy controls (34.84 ± 95.0 vs. 7.65 ± 21.22 pg/ml, p < 0.001; 3.82 ± 0.52 pg/m vs. 1.7 ± 1.7 pg/ml, p < 0.001, respectively). SLE patients had increased percentage of neutrophils in BALF when compared with control group (1.00 ± 5.99 vs. 0.00 ± 0.56 %, p = 0.0003). Pulmonary fibrosis in HRCT was found in 50 % of SLE patients. The disease activity scored by SLAM was significantly higher and total lung capacity was significantly lower in SLE patients with pulmonary fibrosis (8.00 ± 3.17 vs. 6.00 ± 2.31, p = 0.01; 88.00 ± 28.29 vs. 112.00 ± 21.08 % predicted, p = 0.01, respectively). In SLE patients with pulmonary fibrosis, correlations were found between SLAM and IL-8 concentration in BALF, forced expiratory volume in 1 s and forced vital capacity (r = 0.65, p = 0.006; r = -0.53, p = 0.035; r = -0.67, p = 0.006, respectively). Our results indicate that IL-8 plays an important role in the pathogenesis of SLE. An increased concentration of IL-8 according to BALF could be considered as a useful biomarker of SLE activity and pulmonary fibrosis in SLE.

Topics: Adult; Biomarkers; Breath Tests; Bronchoalveolar Lavage Fluid; Disease Progression; Exhalation; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Male; Middle Aged; Pulmonary Fibrosis; Spirometry; Young Adult

Smoke inhalation injury represents a major cause of mortality in burn patients and is associated with a high incidence of pulmonary complications. Glutamine (GLN) is considered a conditionally essential amino acid during critical illness and injury. However, whether GLN could attenuate lung injury caused by smoke inhalation is still unknown. The purpose of this study is to investigate whether GLN has a beneficial effect on smoke inhalation induced lung injury. In our present work, rats were equally randomized into three groups: Sham group (ambient air inhalation plus GLN treatment), Control group (smoke inhalation plus physiological saline) and GLN treatment group (smoke inhalation injury plus GLN treatment). At sampling, bronchoalveolar lavage fluid was performed to determine total protein concentration and pro-inflammatory cytokine levels. Lung tissues were collected for wet/dry ratio, histopathology, hydroxyproline and Western blotting measurement. Our results exhibited that GLN attenuated the lung histopathological alterations, improved pulmonary oxygenation, and mitigated pulmonary edema. At 28days post-injury, GLN mitigated smoke inhalation-induced excessive collagen deposition as evidence by Masson-Goldner trichrome staining and hydroxyproline content. GLN mitigated smoke inhalation-induced lung inflammatory response, and further prevented the activity of NF-kappa-B. More importantly, results from Western blotting and Immunohistochemistry exhibited that GLN enhanced the expression of HSF-1, HSP-70 and HO-1 in lung tissues. Our data demonstrated that GLN protected rats against smoke inhalation-induced lung injury and its protective mechanism seems to involve in inhibition inflammatory response and enhancing HSP expression.

Topics: Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Glutamine; Heme Oxygenase (Decyclizing); HSP70 Heat-Shock Proteins; Hydroxyproline; Interleukin-8; Lung; Male; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Smoke Inhalation Injury

Decision on treatment of systemic sclerosis (SSc) related interstitial lung disease (ILD) largely relies on the findings on high resolution computed tomography (HRCT) and there is a need for improvement in assessment of the fibrotic activity. The objectives of this study were to study biomarkers in bronchoalveolar lavage fluid (BALF) from SSc patients with ILD and to relate the findings to the severity and activity of lung fibrosis.. Fifteen patients with early SSc and 12 healthy controls were subjected to BAL. Cell counts and analyses of CXCL5, CXCL8 and S100A8/A9 were performed in BALF and serum. COMP and KL-6 were measured in serum. HRCT of lungs was quantified for ground glass opacities (GGO), reticulation and traction bronchiectases.. BALF concentrations of CXCL8 (p < 0.001), CXCL5 (p = 0.002) and S100A8/A9 (p = 0.016) were higher in patients than controls. Serum KL-6 (p < 0.001) was increased in SSc patients and correlated with BALF concentration of eosinophils (rS = 0.57, p = 0.027). Patients with more widespread GGO on HRCT were characterised in BALF by a higher eosinophil count (p = 0.002) and in serum by higher KL-6 (p = 0.008). Patients with more fibrosis were characterised in BALF by higher eosinophil count (p = 0.014), higher CXCL8 (p = 0.005) and S100A8A/A9 (p = 0.014) concentration and in serum by a higher serum COMP (p = 0.023).. In SSc related ILD, biomarkers from BALF and serum correlate to findings on HRCT suggesting usefulness as markers of presence and extent of lung fibrosis.

Topics: Adult; Aged; Biomarkers; Bronchoalveolar Lavage Fluid; Calgranulin A; Cartilage Oligomeric Matrix Protein; Case-Control Studies; Chemokine CXCL5; Eosinophils; Female; Humans; Interleukin-8; Leukocyte Count; Longitudinal Studies; Lung Diseases, Interstitial; Male; Middle Aged; Mucin-1; Pulmonary Fibrosis; Scleroderma, Systemic; Severity of Illness Index; Tomography, X-Ray Computed

To study the potential of high-dose N-acetylcysteine (NAC) to attenuate silica-induced pulmonary fibrosis in the rat.. Rats exposed to intratracheal instillation of silica particles were treated with 500 mg/kg NAC orally every day for 7 days, before and up to 28 days after silica administration (n = 32), or received no treatment following silica exposure (n = 32); a third group received intratracheal saline (n = 32). Fibrosis score, and hydroxyproline (HYP) and malondialdehyde (MDA) content, were assessed in lung tissue. Bronchoalveolar lavage fluid (BALF) and serum levels of tumour necrosis factor (TNF)-α, interleukin (IL)-8 and high-sensitivity C-reactive protein (hsCRP) were assessed by enzyme-linked immunosorbent assay.. Histopathology revealed inflammation and fibrosis in lung tissue from rats exposed to silica, but not in saline controls. The fibrosis score was significantly lower in animals treated with NAC compared with silica-exposed untreated rats. HYP and MDA content were significantly lower at all timepoints, following NAC treatment versus no treatment, in silica-exposed rats. NAC attenuated silica-induced increases in TNF-α, IL-8 and hsCRP in BALF and serum.. Oral treatment with high-dose NAC during early silica exposure can ameliorate the activity of proinflammatory cytokines, thus attenuating subsequent lung fibrosis. These results suggest that NAC has potential as a treatment for silica-induced lung fibrosis.

Topics: Acetylcysteine; Administration, Oral; Animals; Antioxidants; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Hydroxyproline; Inflammation; Interleukin-8; Lung; Male; Malondialdehyde; Pulmonary Fibrosis; Rats; Rats, Wistar; Silicon Dioxide; Tumor Necrosis Factor-alpha

Hyaluronan is an important constituent of the extracellular matrix in lungs, and growing evidence demonstrates its important biological properties in the lung. However, its role in interstitial pneumonia remains to be fully clarified. The goal of this study was to clarify the role of hyaluronan in interstitial pneumonia.. Hyaluronan in serum and bronchoalveolar lavage (BAL) fluid of chronic interstitial pneumonia (CIP) patients was measured, and the correlation with clinical parameters was determined. In addition, the correlation between hyaluronan in serum and clinical parameters was analysed in patients with acute exacerbation of interstitial pneumonia (IP-AE).. When compared with healthy controls, serum hyaluronan was significantly greater in patients with CIP and was positively correlated with serum biomarkers of inflammation and fibrosis, such as C-reactive protein and surfactant protein-D. In BAL fluid, the amount of hyaluronan was positively correlated with the percentage of inflammatory cells and the amount of CXCL8. When compared with CIP patients, patients with IP-AE had significantly greater amounts of serum hyaluronan, and patients with the highest serum hyaluronan had the worst 60-day outcomes.. This work suggests that serum hyaluronan may be a clinically useful biomarker of interstitial pneumonia and suggests the possibility that hyaluronan is involved in the pathogenesis of interstitial pneumonia by recruiting inflammatory cells into the lungs.

Topics: Aged; Biomarkers; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Case-Control Studies; Chronic Disease; Female; Humans; Hyaluronic Acid; Interleukin-8; Lung Diseases, Interstitial; Male; Middle Aged; Prognosis; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein D

Idiopathic pulmonary fibrosis continues to be a devastating clinical disorder for which there are few therapeutic options, and the pathogenesis of this disease remains largely unknown. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in cholesterol biosynthesis, and they have been reported to exert pleiotropic effects on the cellular signaling involved in tissue inflammation and in organ fibrosis/remodeling. We examined the preventive effects of statins on fibrogenic mediator expression and production in normal human lung fibroblasts (NHLF).. NHLF were pretreated with 100nM pitavastatin or medium alone (control), and were then stimulated with transforming growth factor-β1 (TGF-β1). mRNA expression and protein secretion of several mediators from cells were analyzed by real-time polymerase chain reaction, enzyme-linked immunosorbent assay or multiplex assay.. TGF-β1-induced expression or production of mediators, such as collagen-1, vascular endothelial growth factor and chemokine C-X-C motif ligand 8, in NHLF pretreated with pitavastatin was significantly suppressed with inhibition of Smad-3 phosphorylation, as compared to untreated controls. In addition, the inhibitory effects of pitavastatin were negated by addition of mevalonate.. Pitavastatin appeared to inhibit TGF-β1-induced fibrogenic mediator production from lung fibroblasts via the mevalonic cascade. Although further evaluation of the signaling pathways for these phenomena is necessary, our results suggest the potential benefits of pitavastatin.

Topics: Cells, Cultured; Collagen; Dose-Response Relationship, Drug; Fibroblasts; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-8; Lung; Mevalonic Acid; Phosphorylation; Pulmonary Fibrosis; Quinolines; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Combined pulmonary fibrosis and emphysema (CPFE) is characterized by upper lobe emphysema together with lower lobe fibrosis. The aim of this study was to examine whether cytokine levels in the alveolar space are associated with emphysematous changes superimposed on pulmonary fibrosis.. Consecutive patients (n = 102), diagnosed with pulmonary fibrosis were retrospectively evaluated. Cytokine levels and differential cell counts in bronchoalveolar lavage (BAL) fluid, pulmonary function, computed tomography (CT) scores and levels of serum markers were compared between patients with or without emphysema.. Among the 102 patients (14 females, mean age 68 years), 38 (37%) had evidence of upper lobe emphysema on computed tomography (CT). Levels of epithelial neutrophil activating peptide 78 (ENA-78/CXCL5) and interleukin (IL)-8/CXCL8 in BAL fluid were significantly higher in patients with emphysema. Vital capacity (VC, % predicted) was greater, and ratio of forced expiratory volume in 1 s/forced vital capacity and diffusing capacity of carbon monoxide (DL(CO))/alveolar volume (V(A)) were lower in patients with emphysema. CXCL8 and CXCL5 levels were associated with percentage or absolute numbers of neutrophils in BAL fluid. In addition, CXCL8 levels were inversely correlated with VC and DL(CO)/V(A), and positively correlated with composite physiological index (CPI) and the extent of areas of low attenuation on CT.. Increased CXC chemokine levels in the airspaces may be associated with emphysematous lung changes in patients with pulmonary fibrosis.

Topics: Aged; Biomarkers; Bronchoalveolar Lavage Fluid; Cell Count; Chemokine CXCL5; Comorbidity; Cytokines; Female; Humans; Interleukin-8; Kaplan-Meier Estimate; Male; Pulmonary Emphysema; Pulmonary Fibrosis; Retrospective Studies; Vital Capacity

The mechanisms leading to the radiation-induced lung responses of alveolitis and fibrosis are largely unknown. Herein we investigated whether CXC receptor 1 and 2 antagonism with CXCL8((3-72))K11R/G31P (G31P), a protein that reduces neutrophil chemotaxis in acute inflammatory response models, decreases the lung response to radiation. Mice of the AKR/J (alveolitis/pneumonitis responding) and KK/HIJ (fibrosis) strains received 18 Gy whole-thorax irradiation and a subset of these mice were treated with G31P (500 µg/kg) three times per week from the day of irradiation until euthanasia due to respiratory distress symptoms or 20 weeks after radiation treatment. Irradiated mice of both strains receiving G31P survived longer than mice receiving radiation alone. Radiation- and G31P-treated AKR/J mice surviving to the end of the experiment developed significantly less alveolitis, as measured histologically, than mice receiving radiation alone, but this difference was not evident in KK/HIJ mice. Using immunohistochemistry, G31P treatment was shown to increase the numbers of Gr-1-positive cells (neutrophils) in the lungs of unirradiated mice relative to control mice injected with saline, but the antagonist did not alter the numbers of Gr-1-positive cells in the lungs of radiation-treated mice. We conclude that G31P treatment reduces radiation-induced alveolitis but not fibrosis in mice.

Topics: Animals; Body Weight; Cell Count; Female; Inflammation; Interleukin-8; Mice; Neutrophils; Peptide Fragments; Phenotype; Pulmonary Alveoli; Pulmonary Fibrosis; Radiation Injuries, Experimental; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Thorax

To explore the effects of high-dose N-acetylcysteine on the lung tissues of rats exposed to silica.. Ninety-six Wistar rats were randomly divided into model group, intervention group and control group (32 rats for each group). The rats of model group and intervention group were exposed to silica by intratracheal infusion of silica dust suspension. The rats in the intervention group were orally given high dose N-acetylcysteine. In 3, 7, 14, 28 days after exposure, eight rats in each group were sacrificed, respectively and the lung samples were collected. The pathological changes of lung were evaluated by HE and Masson staining methods. The levels of TNF-alpha and IL-8 in the BALF were detected by ELISA.. Compared with the control group, the alveolitis and pulmonary fibrosis in the intervention group were significantly reduced. In 3, 7, 14, 28 days after exposure, the lung/body coefficients in the intervention group were 9.30 +/- 0.78, 6.29 +/- 0.74, 7.63 +/- 0.88, 6.06 +/- 1.16 respectively, which were significantly lower than those (13.84 +/- 1.61, 9.23 +/- 0.87, 11.23 +/- 1.25, 9.56 +/- 0.76, P < 0.01 ) in the model group (P < 0.01). At the different time points, the levels of TNF-alpha and IL-8 in the BALF in the intervention group were significantly higher than those in the control group (P < 0.01), but were significantly lower than those in the model group (P < 0.01).. The intervention with high dose N-acetylcysteine can significantly reduce the alveolitis and the TNF-alpha and IL-8 levels in the BALF, therefore, inhibit and delay the development of pulmonary fibrosis of rats exposed to silicon dioxide.

Topics: Acetylcysteine; Animals; Bronchoalveolar Lavage Fluid; Dose-Response Relationship, Drug; Dust; Interleukin-8; Lung; Male; Pulmonary Fibrosis; Rats; Rats, Wistar; Silicon Dioxide; Tumor Necrosis Factor-alpha

To study the roles of macrophage apoptosis, IL-1, and IL-8 in the pathogenesis of rat pulmonary fibrosis induced by silica.. Forty eight male Wistar rats were divided into the 4 control groups (24 rats) and 4 experimental groups (24 rats). Rats in the control groups were treated with 1 ml normal saline by trachea instillation, whereas the rats in experimental groups were exposed 1 ml silica suspension (100 mg/ml) by trachea instillation for 1, 7, 14 and 28 days, respectively. Six rats of each group were sacrificed, then the bronchoalveolar lavage fluid and lung tissues were collected, respectively. Pulmonary inflammation, fibrosis and other pathological changes were detected with H.E. staining. Morphological changes of the early stage apoptosis in macrophages were detected with transmission electron microscope (TEM). The early apoptosis rates of macrophages in BALF were also assessed using Annexin V-FITC/PI kit. The IL-1 and IL-8 levels of serum were measured with the ELISA.. The apoptotic rates (11.48% +/- 0.24%, 16.03% +/- 0.68%, 15.53% +/- 1.07%, 18.92% +/- 2.70%, respectively) of macrophage in the experimental groups increased obviously with time, as compared to the controls (5.47% +/- 2.06%, 6.39% +/- 0.215, 9.07% +/- 0.61% and 8.54% +/- 0.16%, Respectively) (P < 0.05). The IL-1 levels of serum in the experimental groups were 23.64 +/- 0.84, 23.38 +/- 1.10, 22.21 +/- 0.86 and 24.29 +/- 1.31 pg/ml, respectively, which were significantly higher than those (18.52 +/- 1.23, 18.40 +/- 1.6, 17.92 +/- 2.21 and 18.53 +/- 2.64 pg/ml, respectively) in the control groups (P < 0.05) without time-effect relationship. The serum IL-8 levels on the 1st, 7th and 14th days in the experimental groups were 21.32 +/- 1.44, 21.90 +/- 2.08 and 22.00 +/- 2.80 pg/ml, respectively, which were significantly higher than those (17.69 +/- 1.09, 16.98 +/- 2.09 and 17.54 +/- 1.62 pg/ml, respectively) in the control groups (P < 0.05).. The early macrophage apoptosis and changes of IL-1 and IL-8 may in lungs may play an important role in the development of pulmonary fibrosis induced by silica.

Topics: Animals; Apoptosis; Disease Models, Animal; Interleukin-1; Interleukin-8; Macrophages, Alveolar; Male; Pulmonary Fibrosis; Rats; Rats, Wistar; Silicon Dioxide; Silicosis

Angiogenesis-angiostasis balance and leukocyte recruitment are influenced by different concentrations of distinct chemokines.. To investigate the relative contribution of angiogenic and angiostatic CXC chemokines to the pathogenesis of idiopathic pulmonary fibrosis (IPF) and granulomatous lung diseases, we examined the in vitro production of an angiogenic chemokine (IL-8), and 2 angiostatic chemokines (IP-10 and MIG) by alveolar macrophages.. Alveolar macrophages from 16 patients with granulomatous lung diseases [8 with sarcoidosis, 8 with extrinsic allergic alveolitis (EAA)], 16 patients with IPF, and 8 control subjects were cultured for 24 h. IL-8, IL-18, IP-10 and MIG in the culture supernatants were measured by a fluorescent bead-based multiplex technique.. In IPF patients, IL-8 was increased and correlated with bronchoalveolar lavage (BAL) neutrophils, whereas the levels of IP-10 and MIG were normal. In sarcoidosis and EAA patients, IL-8, IP-10, and MIG were all increased and IP-10 and MIG correlated with IL-18, a Th1 cytokine, and the percentage and number of BAL lymphocytes.. The difference in the expression of CXC chemokines and a Th1 cytokine may contribute to the different immunopathogenesis, clinical course and responsiveness to treatment of these diseases.

Topics: Aged; Alveolitis, Extrinsic Allergic; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cells, Cultured; Chemokine CXCL10; Chemokine CXCL9; Eosinophils; Female; Humans; Interleukin-18; Interleukin-8; Male; Neutrophils; Pulmonary Fibrosis; Sarcoidosis, Pulmonary

Activated macrophages have been characterized as M1 and M2 according to their inflammatory response pattern. Here we analyzed the M2 marker expression and intracellular signal transduction in the course of cytokine-driven differentiation. We found elevated spontaneous production of the chemokines CCL17, CCL18 and CCL22 and increased expression of CD206 by alveolar macrophages from patients with lung fibrosis. Stimulation of normal human AM with Th2 cytokines IL-4 and/or IL-10 in vitro revealed IL-4 as the most powerful inducer of M2-phenotype in AM and monocytes. Importantly, IL-10 enhanced IL-4-induced expression of CCL18 and IL-1RA in a synergistic fashion. IL-4/IL-10 stimulation induces a strong activation of STAT3 in AM from fibrosis patients. These results suggest an important role for M2 polarized AM in the pathogenesis of pulmonary fibrosis and indicate that both IL-4 and IL-10 account for human AM phenotype shift to M2, as seen in patients with fibrotic interstitial lung diseases.

Topics: Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Chemokines, CC; Cytokines; Female; Gene Expression; Humans; Idiopathic Pulmonary Fibrosis; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-4; Interleukin-8; Lectins, C-Type; Macrophage Activation; Macrophages, Alveolar; Male; Mannose Receptor; Mannose-Binding Lectins; Middle Aged; Monocytes; Pulmonary Fibrosis; Receptors, Cell Surface; Sarcoidosis, Pulmonary; Scleroderma, Systemic; Signal Transduction; STAT Transcription Factors; Tumor Necrosis Factor-alpha; Young Adult

Dipeptidyl peptidase IV (DP IV)-related proteases and aminopeptidase N (APN) are drug targets in various diseases. Here we investigated for the first time the effects of DP-IV-related protease inhibitors and APN inhibitors on chronic inflammatory lung diseases.. A murine model of silica (SiO2)-induced lung fibrosis and in vitro cultures of human lung epithelial cells and monocytes have been used and the influence of silica-treatment and inhibitors on inflammation and fibrosis has been measured.. We found increased inflammation and secretion of the chemokines IL-6, MCP-1 and MIP-alpha 2 weeks after SiO2 application, and increased lung fibrosis after 3 months. Treatment with the APN inhibitor actinonin reduced chemokine secretion in the lung and bronchoalveolar lavage fluid, and in cell culture, and decreased the level of fibrosis after 3 months. Treatment with inhibitors of DP-IV-related proteases, or a combination of DP IV inhibitors and APN inhibitors, had no significant effect. We found no obvious side effects of long-term treatment with inhibitors of APN and DP IV.. Overall, our findings show that actinonin, an inhibitor of aminopeptidase N, might modulate chemokine secretion in the lung and thus attenuate the development of lung fibrosis. Additional targeting of DP-IV-related proteases had no significant effect on these processes.

Topics: Animals; CD13 Antigens; Cell Line; Cytokines; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hydroxamic Acids; Interleukin-6; Interleukin-8; Lung; Mice; Mice, Inbred C57BL; Protease Inhibitors; Pulmonary Fibrosis; Silicon Dioxide; Transforming Growth Factor beta

Rats exposed to high airborne mass concentrations of low-solubility low-toxicity particles (LSLTP) have been reported to develop lung disease such as fibrosis and lung cancer. These particles are regulated on a mass basis in occupational settings, but mass might not be the appropriate metric as animal studies have shown that nanoparticles (ultrafine particles) produce a stronger adverse effect than fine particles when delivered on an equal mass basis.. This study investigated whether the surface area is a better descriptor than mass of LSLTP of their ability to stimulate pro-inflammatory responses in vitro. In a human alveolar epithelial type II-like cell line, A549, we measured interleukin (IL)-8 mRNA, IL8 protein release and glutathione (GSH) depletion as markers of pro-inflammatory effects and oxidative stress after treatment with a range of LSLTP (fine and nanoparticles) and DQ12 quartz, a particle with a highly reactive surface.. In all the assays, nanoparticle preparations of titanium dioxide (TiO2-np) and of carbon black (CB-np) produced much stronger pro-inflammatory responses than the same mass dose of fine TiO2 and CB. The results of the GSH assay confirmed that oxidative stress was involved in the response to all the particles, and two ultra-fine metal dusts (cobalt and nickel) produced GSH depletion similar to TiO2-np, for similar surface-area dose. As expected, DQ12 quartz was more inflammatory than the low toxicity dusts, on both a mass and surface-area basis.. Dose-response relationships observed in the in vitro assays appeared to be directly comparable with dose-response relationships in vivo when the doses were similarly standardised. Both sets of data suggested a threshold in dose measured as surface area of particles relative to the surface area of the exposed cells, at around 1-10 cm2/cm2. These findings are consistent with the hypothesis that surface area is a more appropriate dose metric than mass for the pro-inflammatory effects of LSLTP in vitro and in vivo, and consequently that the high surface area of nanoparticles is a key factor in their inflammogenicity.

Topics: Cells, Cultured; Dose-Response Relationship, Drug; Epithelial Cells; Glutathione; Humans; Inhalation Exposure; Interleukin-8; Lung Neoplasms; Nanoparticles; Oxidative Stress; Particle Size; Particulate Matter; Pulmonary Fibrosis; Quartz; Respiratory Mucosa; RNA, Messenger; Titanium

The objective of this article was to show the role of cytokines in the pathogenesis of pulmonary fibrosis due to sulfur mustard gas inhalation. Eighteen veterans with mustard gas-induced pulmonary fibrosis and 18 normal patients were used as controls. Bronchoalveolar larvage (BAL) and analyses of BAL fluids for cellular and cytokine levels were performed. There was a significant difference in granulocyte colony stimulating factor (G-CSF) level in the BAL fluid of patients and the controls (p < 0.0001). Granulocyte-macrophage colony stimulating pulmonary fibrosis (GM-CSF) BAL levels were significantly increased in patients with pulmonary fibrosis (PF) in comparison with controls (p < 0.0001). Patients with PF have highly significant increases in IL-8 level compared to controls (87.94 +/- 59.63 vs. 8.66 +/- 6.97 g/mL(1); p < 0.0001) as well. IL-8 and G-CSF levels in BAL fluid correlate only with the percentage and the absolute number of neutrophils of the BAL fluid in patients with PF (p = 0.02/p = 0.01; p = 0.01/p = 0.01; respectively). A significant correlation was found between GM-CSF BAL fluid level and the percentage and the absolute number of the BAL fluid eosinophils (p = 0.04 and p = 0.03). Neutrophils alveolitis, the presence of eosinophils, and higher concentrations of interleukin-8, G-CSF, and GM-CSF in BAL fluid are associated with the development of fibrosis in sulfur mustard victims.

Topics: Adult; Bronchoalveolar Lavage Fluid; Chemical Warfare Agents; Eosinophils; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Leukocyte Count; Male; Middle Aged; Mustard Gas; Neutrophils; Pulmonary Fibrosis; Up-Regulation; Veterans

The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1beta recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1beta production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Bone Marrow Transplantation; Chronic Disease; Disease Models, Animal; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Interleukin-8; Lymphokines; Mice; Mice, Knockout; Myeloid Differentiation Factor 88; Pneumonia; Pulmonary Fibrosis; Receptors, Interleukin-1 Type I; Recombinant Proteins; Respiratory Distress Syndrome; Sialoglycoproteins; Signal Transduction; Transplantation Chimera

To investigate the effect of signal transducer and activator of transcription 1 (STAT1) antisense oligonucleotides (ASON) on secretion of TNF-alpha, IL-8 and NO by alveolar macrophages (AMs) of rats with bleomycin (BLM)-induced pulmonary fibrosis.. Five adult female Wistar rats were intratracheally instilled with BLM. After 7 days, the rats were sacrificed under ketamine anaesthesia and bronchoalveolar lavage (BAL) was performed to obtain AMs. AMs were divided into four groups: STAT1 ASON, STAT1 sense oligonucleotides (SON), dexamethasone (DEX) and control groups. Culture medium was collected at 36 hours after adding STAT1 ASON, STAT1 SON and DEX, respectively. The concentrations of TNF-alpha, IL-8 and NO in the culture medium were detected.. The concentrations of TNF-alpha, IL-8 and NO in STAT1 ASON group were lower than those in STAT1 SON, DEX and control groups (P<0.05). Moreover, the concentrations of TNF-alpha, IL-8 and NO in DEX group were also lower than those in control and STAT1 SON groups (P<0.05). But compared with control group, the concentrations of TNF-alpha, IL-8 and NO in STAT1 SON group was not significantly different (P<0.05).. STAT1 ASON can inhibit the secretion of TNF-alpha, IL-8 and NO in AMs. STAT1 may become a target for treating pulmonary fibrosis.

Topics: Animals; Base Sequence; Bleomycin; Cells, Cultured; Cytokines; Female; Gene Expression Regulation; Interleukin-8; Macrophages, Alveolar; Nitric Oxide; Oligonucleotides, Antisense; Pulmonary Alveoli; Pulmonary Fibrosis; Rats; Rats, Wistar; RNA, Messenger; STAT1 Transcription Factor; Tumor Necrosis Factor-alpha

Recent evidence has shown that several chemokines--including those involved in angiogenesis--have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and sarcoidosis. We speculated that these differences could be attributed to distinct angiogenic and angiostatic profiles. This hypothesis was investigated by estimating the levels of three angiogenic chemokines (growth-related gene [GRO]-alpha, epithelial neutrophil-activating protein [ENA]-78, and interleukin [IL]-8), and three angiostatic chemokines (monokine induced by interferon (IFN)-gamma [MIG], IFN-gamma-inducible protein [IP]-10, and IFN-gamma-inducible T-cell alpha chemoattractant) in serum and BAL fluid (BALF).. We studied prospectively 20 patients with sarcoidosis (median age, 46 years; range, 25 to 65 years), 20 patients with IPF (median age, 68 years; range, 40 to 75 years), and 10 normal subjects (median age, 39 years; range, 26 to 60 years).. The GRO-a serum and BALF levels of IPF patients were found significantly increased in comparison with healthy subjects (799 pg/mL vs 294 pg/mL [p = 0.022] and 1,827 pg/mL vs 94 pg/mL [p < 0.001], respectively) and sarcoidosis patients (799 pg/mL vs 44 pg/mL [p < 0.001] and 1,827 pg/mL vs 214 pg/mL [p < 0.001], respectively). Moreover, ENA-78 and IL-8 BALF levels in IPF patients were significantly higher compared with sarcoidosis patients (191 pg/mL vs 30 pg/mL [p < 0.001] and 640 pg/mL vs 94 pg/mL [p = 0.03], respectively). MIG serum levels in IPF patients were found significantly upregulated in comparison with sarcoidosis patients and healthy control subjects. However, MIG and IP-10 BALF levels (1,136 pg/mL vs 66 pg/mL [p < 0.001] and 112 pg/mL vs 56 pg/mL [p = 0.037], respectively) were significantly higher in sarcoidosis patients compared with IPF patients.. Our data suggest distinct angiogenic profiles between IPF and sarcoidosis, indicating a potential different role of CXC chemokines in the local immunologic response in IPF and pulmonary sarcoidosis.

Topics: Adult; Aged; Angiostatic Proteins; Bronchoalveolar Lavage Fluid; Chemokine CXCL1; Chemokine CXCL10; Chemokine CXCL5; Chemokine CXCL9; Chemokines; Chemokines, CXC; Female; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Lung; Male; Middle Aged; Pulmonary Fibrosis; Reference Values; Sarcoidosis, Pulmonary

To investigate the effect of signal transducers and activators of transcription 1 (STAT1) antisense oligonucleotides (ASON) on concentrations of TNF-alpha, IL-8, NO secreted by alveolar macrophages (AMs) in bleomycin-induced rat pulmonary fibrosis, five adult female Wistar rats were intratracheally instilled with bleomycin. After 7 days, the rats were killed by right ventricle of heart exsanguinations under ketamine anaesthesia and bronchoalveolar lavage (BAL) was performed to obtain AMs. AMs were divided into four groups, treated with STAT1 ASON, STAT1 sense oligonucleotides (SON), dexamethasone (DEX) and medium alone (control), respectively. AMs and media were collected after culture for 36 h. The mRNA and protein expressions of STAT1 and ICAM-1 in AMs were detected by RT-PCR and ELISA, respectively. The concentrations of TNF-alpha, IL-8, NO in cultured medium were detected. The STAT1 mRNA expression by AMs in the STAT1 ASON group was lower than those of AMs in the STAT1 SON group, the DEX group and the control group (p<0.05). Moreover, the STAT1 mRNA expression by AMs in the DEX group was also lower than those of AMs in the STAT1 SON group and the control group (p<0.05), but the STAT1 mRNA expression by AMs in the STAT1 SON group was not different from that of the control group (p>0.05). The protein expressions of STAT1 and ICAM-1 and the mRNA expression of ICAM-1 showed similar changes to the STAT1 mRNA expression by AMs. The concentrations of TNF-alpha, IL-8, NO in cultured medium from STAT1 ASON group were lower than those from STAT1 SON, DEX and the control groups (p<0.05). Moreover, the concentrations of TNF-alpha, IL-8, NO in cultured medium from DEX group were also lower than those from the control and STAT1 SON group (p<0.05), but no difference between STAT1 SON group and the control (p>0.05). The results suggest that STAT1 ASON could inhibit the secretion of TNF-alpha, IL-8, NO in AMs, and STAT1 could become a target of treating pulmonary fibrosis.

Topics: Animals; Bleomycin; Cytokines; Gene Expression Regulation; Intercellular Adhesion Molecule-1; Interleukin-8; Macrophages, Alveolar; Nitric Oxide; Oligonucleotides, Antisense; Pulmonary Fibrosis; Rats; Rats, Wistar; RNA, Messenger; STAT1 Transcription Factor; Tumor Necrosis Factor-alpha

To elucidate the apparent contradictions in vascular remodeling in the lungs of patients with idiopathic pulmonary fibrosis, we evaluated alveolar vascularity in relation to the various degrees of fibrosis in surgically biopsied lungs of usual interstitial pneumonia. Alveolar capillary endothelial cells were intensely immunoreactive with CD34 but not with von Willebrand factor. Vascular density, that is, the relative ratio of capillary area to total area of alveolar walls, was significantly higher at low grades of fibrosis than in control lungs, whereas vascular density gradually decreased as the degree of fibrosis increased and was lower than that of control lungs in the most extensively fibrotic lesions. No vessels were observed inside fibroblastic foci. The potent angiogenic factors vascular endothelial growth factor and interleukin-8 were abundantly produced by capillary endothelial cells and alveolar epithelial cells in highly vascularized alveolar walls. In contrast, venules with CD34-negative but von Willebrand factor-positive endothelial cells localized in the center of the fibrotic lesions were slightly increased and identified as postcapillary venules by three-dimensional reconstructed images. These results indicate the presence of heterogeneous vascular remodeling in usual interstitial pneumonia.

Topics: Antigens, CD34; Biomarkers; Capillaries; Endothelial Cells; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Immunohistochemistry; Interleukin-8; Ki-67 Antigen; Pulmonary Alveoli; Pulmonary Fibrosis; Pulmonary Veins; Severity of Illness Index; Statistics as Topic; Thrombomodulin; Vascular Endothelial Growth Factor A; von Willebrand Factor

Topics: Antigens, CD34; Biomarkers; Capillaries; Endothelial Cells; Humans; Interleukin-8; Ki-67 Antigen; Neovascularization, Pathologic; Pulmonary Alveoli; Pulmonary Fibrosis; Pulmonary Veins; Thrombomodulin; Vascular Endothelial Growth Factor A; von Willebrand Factor

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology. Biopsy and bronchoalveolar lavage studies have shown, that accumulation of inflammatory cells, particularily neutrophils, in the alveolar space is a relevant feature of the pathogenesis of IPF. This paper adresses the issue of whether the safe and non-invasive method of sputum induction is a suitable tool to study respiratory tract inflammation in IPF.. In a cross-sectional analysis, 15 IPF patients and 14 healthy, non-smoking subjects underwent sputum induction. Total sputum cell counts, differentials, and the amount of interleukin (IL)-8, granulocyte-macrophage-colony stimulating factor (GM-CSF), and soluble ICAM-1 (sICAM) in sputum supernatant were analyzed.. IPF patients had increased sputum neutrophils (60 +/- 6 vs 22 +/- 3%, p = 0.0003), and supernatant concentrations of IL-8 (19 +/- 3 vs. 7 +/- 1 ng/ml, p = 0.0002), GM-CSF (205 +/- 43 vs. 122 +/- 36 pg/ml, p = 0.08) and sICAM (12 +/- 3 vs. 5 +/- 3 ng/ml, p = 0.01), when compared with healthy controls. Sputum IL-8 was correlated with sputum neutrophils (rho = 0.61, p = 0.0006) in all patients. The extent of sputum neutrophilia was also correlated with lung function impairment (vital capacity, % of predicted) in IPF patients (rho = -0.68, p = 0.007).. These data confirm the established role of neutrophilic inflammation in the pathogenesis of IPF, and show the potential of induced sputum to directly study inflammatory processes and surrogate markers in interstitial lung diseases like IPF.

Topics: Adult; Aged; Biomarkers; Cross-Sectional Studies; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Middle Aged; Neutrophil Activation; Pulmonary Fibrosis; Sputum

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory process characterized by severe derangement of gas exchange in the advanced stages of disease. However, erythrocytosis is infrequent in IPF. The aim of this study was to investigate the potential relation between the blunted erythropoietic response and the chronic inflammation.. Nine patients (6 men and 3 women) with IPF and profound hypoxemia (PO(2) < 65 mm Hg) and 34 sex- and age-matched healthy volunteers participated in the study.. We evaluated the hematologic parameters, serum erythropoietin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 levels. We also studied the development of burst-forming unit-erythroid (BFU-E)-derived colonies in semisolid methylcellulose cultures in blood samples from all patients.. Hemoglobin and serum erythropoietin levels were almost comparable between the two studied groups. On the contrary, serum TNF-alpha, IL-6, and IL-8 values were significantly higher in patients with IPF (p < 0.05, p < 0.01, and p < 0.001, respectively). IPF sera induced a significant growth inhibition of erythroid bursts arising from mononuclear cells of either patients or control subjects compared with heat-inactivated AB serum (p < 0.05 and p < 0.01, respectively). Moreover, there was an apparent increment in the number of BFU-E colonies when patients' mononuclear cells were cultured in comparison with those of healthy subjects (p < 0.05).. Our findings suggest that in IPF there is an increased number of primitive erythroid progenitors, which fail to proliferate and differentiate in vivo, suggesting a kind of ineffective erythropoiesis. As a consequence, hemoglobin levels do not rise in proportion to the severity of hypoxemia. Cytokines released from alveolar macrophages seem to have not only local but also systemic effects, since the serum of these patients directly suppressed erythropoiesis; however, the suboptimal erythropoietic response to hypoxia cannot be entirely attributed to this suppression. It is possible that several other factors interfere, synergistically or additively.

Topics: Aged; Case-Control Studies; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Pulmonary Fibrosis; Tumor Necrosis Factor-alpha

The levels of interleukin-8 (IL-8) in the serum, bronchoalveolar fluid (BALF) and epithelial lining fluid (ELF) were measured in patients with idiopathic pulmonary fibrosis. (IPF), in order to evaluate the clinical significance of IL-8. The serum levels were significantly higher in patients with active IPF (34.4 +/- 11.9 pg/ml, n = 8) than in those with stable IPF (mean: 14.6 +/- 10.9 pg/ml, n = 18), but neither correlated with the serum level of KL-6 or of SP-D, or with the intensity of chest Ga67-scintigraphy. There were no significant differences in BALF or ELF IL-8 levels between the active and stable IPF groups. These results suggest that the serum level of IL-8 is a useful marker for evaluating the disease activity in patients with IPF.

Topics: Aged; Body Fluids; Bronchoalveolar Lavage Fluid; Female; Humans; Interleukin-8; Male; Middle Aged; Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal disorder. Fibroplasia and deposition of extracellular matrix are dependent, in part, on angiogenesis and vascular remodeling. We obtained open lung biopsies from patients undergoing thoracic surgery for reasons other than interstitial lung disease (control) (n = 78) and from patients with IPF (n = 91). We found that levels of epithelial neutrophil-activating peptide 78 (ENA-78) were greater from tissue specimens of IPF patients, as compared with control subjects. When ENA-78 was depleted from IPF tissue specimens, tissue-derived angiogenic activity was markedly reduced. Immunolocalization of ENA-78 demonstrated that hyperplastic Type II pneumocytes and macrophages were the predominant cellular sources of ENA-78. These findings support the notion that ENA-78 may be an important additional factor that regulates angiogenic activity in IPF.

Topics: Angiogenesis Inducing Agents; Animals; Chemokine CXCL5; Chemokines, CXC; Cornea; Enzyme-Linked Immunosorbent Assay; Epithelium; Fibroblasts; Humans; Interleukin-8; Lung; Macrophages; Neovascularization, Pathologic; Pulmonary Fibrosis; Rats; Rats, Long-Evans

To search for single-nucleotide polymorphisms in the interleukin-8 (IL-8) and IL-8 receptor CXCR-1 and CXCR-2 genes, and to compare their distribution among patients with systemic sclerosis (SSc) with fibrosing alveolitis (FASSc) or without fibrosing alveolitis (NFASSc), or patients with cryptogenic fibrosing alveolitis (CFA), and normal healthy subjects.. Fifty control subjects were screened for potential polymorphisms by using polymerase chain reaction in association with sequence-specific primers incorporating mismatches at the 3' end. The novel polymorphisms were subsequently examined in British Caucasian subjects, including 194 healthy controls, 71 patients with CFA, and 128 patients with SSc who were further subdivided into 78 FASSc patients and 50 NFASSc patients.. Three novel biallelic polymorphisms were identified in the IL-8 gene (all in noncoding areas of the gene), 1 was found in the CXCR-1 gene (resulting in a conservative amino acid change), and 3 were observed in the CXCR-2 gene, of which the first resulted in a silent codon change and the others were in the 3' untranslated area of exon 3. Compared with controls, a significant increase in the frequency of the CXCR-2 +785 CC homozygote and of the CXCR-2 +1208 TT homozygote was found in the SSc patients (37% versus 22% [P = 0.01] and 33% versus 17% [P = 0.003], respectively). A subgroup analysis revealed this association to be significant both in the FASSc patients and in the NFASSc patients.. This report describes an association between SSc and 2 polymorphisms occurring close to each other in the CXCR-2 gene. This finding and its functional significance need to be confirmed and analyzed in future studies.

Topics: Antigens, CD; DNA; DNA Primers; Electrophoresis, Agar Gel; Female; Heterozygote; Homozygote; Humans; Interleukin-8; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Pulmonary Fibrosis; Receptors, Chemokine; Receptors, Interleukin; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Scleroderma, Systemic

The effects of a second generation p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridim idi n-4-yl)imidazole; IC(50) = 44 nM vs. p38 alpha], were assessed in models that represent different pathological aspects of chronic obstructive pulmonary disease (COPD) [airway neutrophilia, enhanced cytokine formation and increased matrix metalloproteinase (MMP)-9 activity] and in a model of lung fibrosis. Airway neutrophil infiltration and interleukin (IL)-6 levels, assessed by bronchoalveolar lavage 48 h after lipopolysaccharide (LPS) inhalation, were inhibited dose dependently by 3-30 mg/kg of SB 239063 given orally twice a day. In addition, SB 239063 (30 mg/kg orally) attenuated IL-6 bronchoalveolar lavage fluid concentrations (>90% inhibition) and MMP-9 activity (64% inhibition) assessed 6 h after LPS exposure. In guinea pig cultured alveolar macrophages, SB 239063 inhibited LPS-induced IL-6 production (IC(50) of 362 nM). In a bleomycin-induced pulmonary fibrosis model in rats, treatment with SB 239063 (2.4 or 4.8 mg/day via osmotic pump) significantly inhibited bleomycin-induced right ventricular hypertrophy (indicative of secondary pulmonary hypertension) and increases in lung hydroxyproline synthesis (indicative of collagen synthesis and fibrosis). Therefore, SB 239063 demonstrates activity against a range of sequelae commonly associated with COPD and fibrosis, supporting the therapeutic potential of p38 MAPK inhibitors such as SB 239063 in chronic airway disease.

Topics: Animals; Bleomycin; Cells, Cultured; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Guinea Pigs; Humans; Hypertension, Pulmonary; Imidazoles; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Lung Diseases, Obstructive; Male; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinases; Neutrophils; p38 Mitogen-Activated Protein Kinases; Pulmonary Alveoli; Pulmonary Fibrosis; Pyrimidines; Rats; Rats, Inbred Lew; Sialoglycoproteins; Tumor Necrosis Factor-alpha

Accumulation of monocytes and neutrophils and fibrous distortion of the airway are characteristics of airway disease secondary to smoking. The presence of inflammatory cells and fibrosis correlate, and, therefore, we postulated that lung fibroblasts might release chemotactic activity for neutrophils and monocytes in response to smoke extract. To test this hypothesis, human fetal lung (HFL1) fibroblasts were cultured, and the supernatant fluid was evaluated for neutrophil (NCA) and monocyte (MCA) chemotactic activities with a blind well chamber technique. HFL1 fibroblasts released chemotactic activity in response to smoke extract in a dose- and time-dependent manner (P < 0.05). Checkerboard analysis showed that the activity was predominantly chemotactic. Partial characterization of the released chemotactic activity revealed that the activity was partly heat labile, trypsin sensitive, and ethyl acetate extractable. Lipoxygenase inhibitors and cycloheximide inhibited the release of both NCA and MCA. Molecular-sieve chromatography revealed that NCA and MCA were heterogeneous. NCA was inhibited by anti-human interleukin (IL)-8 and anti-granulocyte colony-stimulating factor antibodies and a leukotriene (LT) B(4)-receptor antagonist. Anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) and anti-monocyte chemoattractant protein (MCP)-1 antibodies and an LTB(4)-receptor antagonist inhibited MCA. Immunoreactive IL-8, granulocyte colony-stimulating factor, GM-CSF, and MCP-1 significantly increased in culture supernatant fluid in response to smoke extract. Finally, smoke extract augmented the expression of mRNAs of IL-8, GM-CSF, and MCP-1. These data demonstrate that lung fibroblasts release NCA and MCA in response to smoke extract and suggest that lung fibroblasts may modulate the inflammatory cell recruitment into the lung.

Topics: Cells, Cultured; Chemokine CCL2; Chemokine CCL5; Chemotaxis; Chromatography; Cycloheximide; Fibroblasts; Gene Expression; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Interleukin-8; Isoquinolines; Leukotriene B4; Lung; Monocytes; Neutrophils; Nicotiana; Phenylpropionates; Plants, Toxic; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Protein Synthesis Inhibitors; Pulmonary Fibrosis; Pyridinium Compounds; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Smoking; Tetrahydroisoquinolines; Transforming Growth Factor beta

The alveolar macrophage (AM) secretes interleukin 1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8), all of them inflammatory cytokines involved in the pathogenesis of many lung diseases. The aim of the present work was to evaluate the basal and stimulated secretion of these cytokines by human AMs. Human AMs were collected by bronchoalveolar lavage (BAL) from four healthy controls and 13 patients with diffuse interstitial lung disease (five cases of sarcoidosis, three of hypersensitivity pneumonitis and five of idiopathic pulmonary fibrosis). AMs were cultured in the presence or absence of different concentrations of lipopolysaccharide (LPS), phorbolmyristate and gamma-interferon. IL-1beta, TNF-alpha, IL-6 and IL-8 levels were measured in BAL fluid and culture supernatant using specific enzyme-linked immunosorbent assays. The substance found to stimulate the secretion of inflammatory cytokines to the greatest extent was LPS at a concentration of 10 microg/ml. Regarding the secretion of IL-1beta, four observations were of interest: basal secretion was very low; LPS exerted a potent stimulatory effect; considerable within-group variability was observed; and there were no significant differences in the comparisons among groups. With respect to TNF-alpha secretion, the results were similar. The only striking finding was the higher basal secretion of this cytokine with respect to that of IL-1beta. Regarding the secretion of IL-6, the same pattern followed by TNF-alpha was found. However, it should be stressed that the increase induced by LPS was smaller than in the two previous cytokines. Regarding the secretion of IL-8, three findings were patent: the strong basal secretion of this cytokine; the moderate increase induced by LPS; and the existence of significant differences among the different groups with respect to the stimulated secretion of this cytokine, which reached maximum values in patients with idiopathic pulmonary fibrosis. Finally, it should be noted that the pattern of cytokines observed in the BAL fluid was similar to that found in cultured AM supernatants. The pattern of inflammatory cytokine secretion by AMs differs from that of other cells of the mononuclear phagocyte system (MPS). In this sense. AMs secrete low amounts of IL-1, moderate amounts of TNF-alpha and IL-6, and high quantities of IL-8. Adherence is an important stimulus in the secretion of these molecules and LPS elicits an incr

Topics: Alveolitis, Extrinsic Allergic; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cells, Cultured; Chemokines; Cough; Humans; Interferon-gamma; Interleukin-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Macrophages, Alveolar; Pulmonary Fibrosis; Reference Values; Sarcoidosis; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

To evaluate the role of cytokines released by the inflammatory cells and immunocytes from patients in pathogenesis of developing sarcoidosis.. With well- microchemotaxis and allergy immunology, the level of tumor necrosis factor-alpha (TNF-alpha) and neutrophil chemotactic factor (NCF) was measured in the serum and BALF of 11 sarcoidosis and 7 IPF and 8 normal subjects (non-smokers).. The levels of TNFalpha (11.9 +/- 3.2, 11.7 +/- 3.0 ng x L(-1)) and NCF (191 +/- 51, 203 +/- 44 cell x 10HP(-1)) of BALF in the patients with sarcoidosis and IPF were significantly higher than these in control group (P < 0.01) and were higher than those in serum. The level of TNF-alpha in the BALF of patients with sarcoidosis was positively correlated with the percentage of lymphocytes (r = 0.73, P < 0.01). The activity of NCF in the BALF of patients with IPF was positively correlated with the percentage of neutrophils (r = 0.89, P < 0.01).. It indicated that TNF-alpha and NCF might play an important role in the pathogenetic process of the sarcoidosis and IPF, and can act as the marker of activity of these diseases.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Female; Humans; Interleukin-8; Male; Middle Aged; Pulmonary Fibrosis; Sarcoidosis, Pulmonary; Tumor Necrosis Factor-alpha

The purpose of the present study was to clarify the consecutive changes and roles of hyaluronan (HA), interleukin-8 (IL-8) and collagen production by lung fibroblasts in the course of pulmonary fibrosis.. Quantitative and comparative assessments of the HA, IL-8 and collagen (presented by hydroproline; HYP) levels in lung fibroblast-conditioned media were made at various stages during the development of bleomycin-induced pulmonary fibrosis in rats.. In lung fibroblast-conditioned media of bleomycin-treated animals: (1) The HA levels increased significantly on day 1, peaked on day 3, and then gradually declined and returned to control values on days 14 - 28. (2) The IL-8 levels strikingly increased on day 1, reached the peak values on day 7, thereafter, gradually decreased, regained control values by day 28. (3) The collagen levels increased significantly on day 7, peaked on day 14, and then gradually declined, However, remained significantly above normal values on day 28. (4) In bleomycin group, the HA and IL-8 levels both significantly correlated to cell components in BALF.. The lung fibroblasts were activated, produced increased HA and IL-8, and were the main source of HA and IL-8 within the lung in the early stage of pulmonary fibrosis; increased HA and IL-8 synthesis of lung fibroblasts might reflect the intensity of alveolitis and the disease activity; The excessive collagen deposition within the lung primarily occurred at the middle stage of pulmonary fibrosis.

Topics: Animals; Bronchoalveolar Lavage Fluid; Collagen; Fibroblasts; Hyaluronic Acid; Hydroxyproline; Interleukin-8; Lung; Pulmonary Fibrosis; Rats; Rats, Wistar

It has been shown that interleukin 8 (IL-8) is increased in bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF) and there is increasing evidence that it is involved in the pathogenesis of this disease. To date, no data are available as to whether IL-8 is elevated in sera of IPF patients. We obtained sera from 42 patients with IPF and 20 healthy controls at time of BAL. From 20 of 42 patients with IPF and 12 of 20 controls BALF was available, enabling us to measure IL-8 in serum and BALF of the same time point. IL-8 was significantly elevated in serum (54.7 +/- 7.5 pg/ml, p < 0.0001) and BALF (715.7 +/- 112.4 pg/ml, p < 0.0001) of patients with IPF compared with controls (IL-8 in serum, 5.2 +/- 0.8 pg/ml; IL-8 in BALF, 67.3 +/- 9.7 pg/ml). We observed a significant positive correlation between IL-8 levels in BALF and percentage of BALF neutrophils (p < 0.001) and between serum IL-8 and BALF IL-8 levels (p < 0.005) in patients with IPF. Consequently, the serum IL-8 level correlated positively with the percentage of BAL neutrophils (p < 0.01), indicating that it may reflect the degree of neutrophilic alveolitis in IPF. Furthermore, the serum IL-8 level showed a negative correlation with important indicators of impairment of lung function (DL(CO), TLC, VC) and PaO2. In conclusion, we were able to demonstrate that the degree of neutrophilic alveolitis in IPF is reflected by increased serum levels of IL-8 and we suggest that the serological assessment of IL-8 may provide a useful parameter for clinicians in monitoring patients with IPF.

Topics: Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; CD4-CD8 Ratio; Cell Count; Eosinophils; Female; Glucocorticoids; Humans; Interleukin-8; L-Lactate Dehydrogenase; Leukocyte Count; Lymphocyte Count; Macrophages, Alveolar; Middle Aged; Neutrophils; Oxygen; Prednisolone; Pulmonary Alveoli; Pulmonary Diffusing Capacity; Pulmonary Fibrosis; Total Lung Capacity; Vital Capacity

Interleukin-8 (IL-8) is a neutrophilic chemotactic factor which may have a prominent role in the attraction of neutrophils to the lung in idiopathic pulmonary fibrosis (IPF). The objective of this study was to investigate the usefulness of IL-8 expression in bronchoalveolar lavage (BAL) cells in the evaluation of alveolitis in IPF. We analysed the BAL cell expression of IL-8 by immunocytochemistry in 19 patients with IPF (six smokers, three ex-smokers and ten non-smokers) and in a control group composed of 14 individuals (six smokers, eight non-smokers). In IPF, BAL was performed on both the pulmonary lobe with the most extensive involvement and the one less extensively involved on high-resolution computed tomography (HRCT) scans. The percentages and absolute numbers of BAL IL-8+ macrophages from lobes with the most extensive HRCT scan involvement (36 +/- 6% and (6 +/- 2 x 10(4) ml-1) (SE) and from those less extensively involved [26% +/- 4% and (6 +/- 1) x 10(4) ml-1] were significantly higher with respect to both those from healthy smokers [17% +/- 6% and (7 +/- 4) x 10(4) ml-1] and those from non-smokers [2% +/- 1% and (1 +/- 0.3) x 10(4) ml-1] (P = 0.005 and P = 0.001, respectively), without differences between the two lobes. In contrast, both the proportions and the absolute numbers of BAL neutrophils in IPF were significantly higher in lobes with the most extensively involved HRCT scan in comparison with lobes with the least extensive involvement [13% +/- 3%, (3 +/- 1) x 10(4) ml-1 vs. 8% +/- 2%, (1 +/- 0.3) x 10(4) ml-1, P = 0.05]. Moreover, the numbers of BAL neutrophils, but not those of IL-8+ macrophages, correlated with the extent of total pulmonary HRCT scan abnormalities in the most involved lobe (r = 0.64, P = 0.04). A correlation between neutrophils and IL-8+ cells was not observed. The results of this study suggest that, in IPF, BAL neutrophilia offers a better description of the disease inflammatory process than the expression of IL-8 in BAL cells.

Topics: Aged; Biomarkers; Bronchoalveolar Lavage Fluid; Female; Humans; Interleukin-8; Leukocyte Count; Male; Middle Aged; Neutrophils; Predictive Value of Tests; Pulmonary Alveoli; Pulmonary Fibrosis; Respiratory Function Tests; Statistics, Nonparametric; Tomography, X-Ray Computed

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.

Topics: Adult; Aged; Antibodies; Bronchoalveolar Lavage Fluid; Calcium; Chemotaxis, Leukocyte; Eosinophils; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Intracellular Membranes; Male; Middle Aged; Osmolar Concentration; Pulmonary Fibrosis

There is increasing evidence that the proinflammatory chemokines interleukin-8 (IL-8) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are involved in the pathogenesis of interstitial lung diseases.. We investigated the release of TNF-alpha, IL-8, MIP-1 alpha by cultured bronchoalveolar lavage (BAL) immune cells of patients with idiopathic pulmonary fibrosis (IPF, n = 24), sarcoidosis (SAR, n = 24), and controls (n = 20) by ELISA. Furthermore, mRNA expression of these cytokines in BAL cells immediately frozen after bronchoscopy was determined. The clinical course of the disease was evaluated and the patients were subdivided into groups with progressing or stable disease.. TNF-alpha, IL-8, and MIP-1 alpha were significantly elevated in the supernatants of BAL immune cells of IPF and SAR patients with progressing disease compared to controls (p < 0.005 in both diseases) and also when compared to patients with stable disease (IPF p < 0.005, SAR p < 0.05). Interestingly, the release of TNF-alpha, IL-8, and MIP-1 alpha did not differ significantly between IPF patients with stable disease and controls, whereas in SAR patients with stable disease a difference at a low significance level (p < 0.05) was obtained. In IPF and SAR patients with progressing disease, a clear mRNA signal of TNF-alpha, IL-8, and MIP-1 alpha was detected in BAL immune cells not having been stimulated by adherence to plastic, whereas in patients with stable disease or controls only a weak signal was observed. MIP-1 alpha release correlated positively with percentage of BAL eosinophils in IPF and SAR. Furthermore, the percentage of eosinophils in BAL was significantly elevated in the IPF subgroup with progressing disease.. Our data demonstrate that an exaggerated expression of TNF-alpha, IL-8, and MIP-1 alpha in BAL immune cells is characteristic for IPF and SAR patients who show progressing disease.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Chemokine CCL4; Chemokines; Humans; Interleukin-8; Macrophage Inflammatory Proteins; Middle Aged; Pulmonary Fibrosis; RNA, Messenger; Sarcoidosis; Tumor Necrosis Factor-alpha

Cyclosporin A (CsA) is an immunomodulator drug that has been used in the treatment of several types of advanced pulmonary interstitial disease. This beneficial effect occurs mainly in circumstances in which alveolitis due to CD4 lymphocytes is absent, suggesting that CsA acts on other types of cells. The present study was undertaken to determine the effect of CsA on inflammatory cytokine secretion by human alveolar macrophages (AMs). Human AMs were collected by bronchoalveolar lavage from four control subjects and 13 patients with interstitial lung disease. Purified human AMs were incubated with different concentrations of CsA (200, 20 and 2 ng ml-1) in the presence or absence of lipopolysaccharide (LPS). Interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), IL-6 and IL-8 levels were measured in supernatants using specific enzyme-linked immunosorbent assays. It was found that CsA inhibits basal secretion of TNF-alpha and IL-8 at 20 and 200 ng ml-1. However, none of the different concentrations of CsA modified basal secretion of IL-1 beta nor IL-6. By contrast, a lower concentration of CsA (2 ng ml-1) inhibits LPS-stimulated secretion of all inflammatory cytokines. It is concluded that CsA exerts a modest effect on inflammatory cytokine production by human AMs.

Topics: Alveolitis, Extrinsic Allergic; Cells, Cultured; Cyclosporine; Cytokines; Humans; Immunosuppressive Agents; Interleukin-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung Diseases, Interstitial; Macrophages, Alveolar; Pulmonary Fibrosis; Sarcoidosis; Tumor Necrosis Factor-alpha

It has well been known that cytokines and extracellular matrix protein (ECM) have played an important role in pulmonary fibrosis in animal model as well as in patients. The purpose of this study was to evaluate the suppressive effect of colchicine (Colc.) in bleomycin (BLM)-treated rats.. Consecutive changes of interleukin-6(IL-6) and interleukin-8 (IL-8) released by alveolar macrophage (AM) were measured with murine B-cell hybridoma 7TD1 cells and micro membrane filter test. ECM and lipid peroxidation were observed with radioimmunoassay and biochemical assay respectively.. (1) Colc. significantly suppressed release of IL-6 by AM from day 7 to 28 (P < 0.05). But the level of IL-6 remained higher than that of the control. On the day 1 to 3, IL-8 released by AM markedly decreased (P < 0.01) and the peak of IL-8 secretion had not appeared. (2) Colc. had no protective effects on AM lipid peroxidation injury. (3) Colc. markedly decreased the level of fibronectin (FN) by AM on day 7, 14 (P < 0.01), as well as the level of laminin (LN) in bronchoalveolar lavage fluid (BALF) on day 7 to 28. However, the level of LN remained higher than that of control. (4) Colc. lessened the collagen deposition, and the lung hydroxyproline (HYP) content decreased on day 7, 14 and 28 (P < 0.05) compared with that of the control. (5) Colc. decreased exudation of inflammatory cells in the early response, as well as the degree of fibrosis in the late stage.. Lipid peroxidation of AM might be one of the mechanisms of tissue injury and of AM activation, which increases the release of cytokines (IL-6, IL-8) and deposition of extracellular matrix proteins (FN, LN). Colc. exertes somewhat inhibitory effects on the process of pulmonary fibrosis in animal model. Factors other than AM and its cytokines might also be involved in the pathogenesis of pulmonary fibrosis in experimental rats.

Topics: Animals; Bleomycin; Colchicine; Female; Fibronectins; Interleukin-6; Interleukin-8; Laminin; Macrophages, Alveolar; Pulmonary Fibrosis; Random Allocation; Rats; Rats, Wistar

To investigate the relationship between the level of the neutrophil chemotactic factor(NCF), tumor necrosis factor-alpha(TNF-alpha) in patients with interstitial lung disease(ILD) and the activity of ILD.. The NCF activities in the BALF and in the serum from 11 patients with sarcoidosis, 7 with idiopathic pulmonary fibrosis (IPF) and 8 normal subjects were determined using the membrane filter and radio-immunoassay. The level of TNF-alpha was also detected.. In the 7 IPF patients, the level of NCF and TNF-alpha (203 +/- 44 cells/10 HP, 11.7 +/- 2.9 ng/L) in the BALF was higher than that in 8 control patients (83 +/- 45 cells/10 HP, 6.5 +/- 1.4 ng/L, P < 0.01). The level of NCF and TNF-alpha in the BALF from 11 patients with sarcoidosis (186 +/- 50 cells/10 HP, 12 +/- 3 ng/L) was highet than those in 8 control patients (P < 0.01). The level of NCF and TNF-alpha in the BALF from patients with IPF was positive correlated with the percentage of neutrophil (NCF: r = 0.89, P < 0.01; TNF-alpha: r = 0.86, P < 0.05). The level of NCF and TNF-alpha in the BALF of patients with sarcoidosis was positive correlated with the percentage of lymphocyte (NCF: r = 0.78, P < 0.01; TNF-alpha: r = 0.73, P < 0.01.. The level of NCF and TNF-alpha in the BALF from patients with IPF and sarcoidosis can act as the marker of the activity of alveolitis of IPF and sarcoidosis.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Female; Humans; Interleukin-8; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neutrophils; Pulmonary Fibrosis; Sarcoidosis, Pulmonary; Tumor Necrosis Factor-alpha

Neutrophil accumulation in the lower respiratory tract of patients with fibrosing alveolitis is thought to be facilitated by IL-8, a neutrophil chemoattractant primarily secreted by mononuclear phagocytes. The aims of this study were: (i) to explore IL-8 secretion by lung and blood mononuclear phagocytes in subjects with cryptogenic fibrosing alveolitis, systemic sclerosis with and without fibrosing alveolitis, sarcoidosis and normal individuals; (ii) to examine IL-8 secretory heterogeneity in alveolar macrophages and peripheral blood monocytes; and (iii) to correlate alveolar macrophage phenotypic profile to IL-8 secretion. We observed that more monocytes secreted IL-8 than autologous macrophages and that there was heterogeneity in the in vitro IL-8 secretion by alveolar macrophages and peripheral blood monocytes. IL-8 secretion by alveolar macrophages was significantly higher in subjects with fibrosing alveolitis compared with subjects without fibrosing alveolitis, due to a higher percentage of IL-8-secreting alveolar macrophages in the fibrotic group both in the absence (P < 0.002) and presence of lipopolysaccharide (LPS) (P < 0.04) and correlated with bronchoalveolar lavage neutrophil percentage. Using the MoAbs RFD1, RFD7 and RFD9, that distinguish subsets of alveolar macrophages, we have been able to identify associations between secretion of IL-8 and smaller cells and the cells identified by the MoAb RFD7. In situ hybridization of the bronchoalveolar lavage cell population revealed that alveolar macrophages are the predominant source of IL-8 in the lung. We conclude that there is an increased number of IL-8-secreting alveolar macrophages in the lungs of patients with fibrosing alveolitis, and IL-8 secretion by these cells is associated with specific phenotypic profile expression.

Topics: Adult; Aged; Animals; Bronchoalveolar Lavage; Erythrocytes; Female; Humans; Immunophenotyping; In Situ Hybridization; Interleukin-8; Lung; Macrophages, Alveolar; Male; Middle Aged; Monocytes; Neutrophils; Phagocytes; Pulmonary Fibrosis; Sheep; Up-Regulation

Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal disorder. Fibroplasia and deposition of extracellular matrix are dependent, in part, on angiogenesis. We postulated that an imbalance exists in the expression of angiogenic (IL-8) vs angiostatic (IFN-gamma-inducible protein (IP-10)) CXC chemokines, which favors net angiogenesis in IPF. To test this hypothesis, we obtained open lung biopsies either from normal patients undergoing thoracic surgery for reasons other than interstitial lung disease (control) or from patients with IPF. We found that levels of IL-8 were greater from tissue specimens of IPF patients then from those of controls. In contrast, IP-10 levels were higher from tissue specimens obtained from control subjects than from those from IPF patients. When IL-8 or IP-10 was depleted from IPF tissue specimens, tissue-derived angiogenic activity was markedly reduced or enhanced, respectively. Immunolocalization of IL-8 demonstrated that the pulmonary fibroblast (PF) of IPF lung was the predominant cellular source of IL-8. Isolated PF from IPF patients constitutively produced more IL-8 and less IP-10 than control PF. Conditioned media from IPF-PFs demonstrated constitutive angiogenic activity that was attributable, in part, to IL-8. Depletion of IP-10 from IPF-PF CM resulted in an increase in corneal neovascularization. These findings support the notion that IL-8 and IP-10 are important factors that regulate angiogenic activity in IPF.

Topics: Aged; Cell Separation; Chemokine CXCL10; Chemokines; Chemokines, CXC; Culture Media, Conditioned; Cytokines; Fibroblasts; Humans; Interferon-gamma; Interleukin-8; Lung; Middle Aged; Neovascularization, Pathologic; Pulmonary Fibrosis

This study was designed to clarify the contribution of IL-8 as a specific neutrophil chemotactic factor in the human respiratory tract in various pulmonary diseases. The neutrophil chemotactic activity (NCA), neutrophil counts and IL-8 concentration in the bronchoalveolar lavage fluid (BALF) obtained from normal volunteers (NV), control patients (CP), patients with diffuse panbronchiolitis (DPB) and patients with idiopathic pulmonary fibrosis (IPF) were examined. Neutrophil counts, NCA and IL-8 concentration in BALF obtained from patients with DPB or IPF was significantly higher than that from NV or CP. The IL-8 concentration correlated with neutrophil count and also correlated with NCA in BALF from patients with IPF, whereas there was no correlation between these factors in BALF from DPB. These results suggest that the contribution of IL-8 to neutrophil accumulation of the lower respiratory tract is different between IPF and DPB.

Topics: Blood Cell Count; Bronchoalveolar Lavage; Chemotaxis; Humans; Interleukin-8; Neutrophils; Pulmonary Fibrosis

Hyaluronan (HA) is a glycosaminoglycan constituent of extracellular matrix. In its native form HA exists as a high molecular weight polymer, but during inflammation lower molecular weight fragments accumulate. We have identified a collection of inflammatory genes induced in macrophages by HA fragments but not by high molecular weight HA. These include several members of the chemokine gene family: macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, cytokine responsive gene-2, monocyte chemoattractant protein-1, and regulated on activation, normal T cell expressed and secreted. HA fragments as small as hexamers are capable of inducing expression of these genes in a mouse alveolar macrophage cell line, and monoclonal antibody to the HA receptor CD44 completely blocks binding of fluorescein-labeled HA to these cells and significantly inhibits HA-induced gene expression. We also investigated the ability of HA fragments to induce chemokine gene expression in human alveolar macrophages from patients with idiopathic pulmonary fibrosis and found that interleukin-8 mRNA is markedly induced. These data support the hypothesis that HA fragments generated during inflammation induce the expression of macrophage genes which are important in the development and maintenance of the inflammatory response.

Topics: Animals; Antibodies, Blocking; Antibodies, Monoclonal; Blotting, Northern; Bronchoalveolar Lavage; Cells, Cultured; Chemokine CCL2; Chemokine CCL4; Chemokine CCL5; Chemokine CXCL10; Gene Expression Regulation; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Hyaluronan Receptors; Hyaluronic Acid; Inflammation; Interleukin-8; Macrophage Inflammatory Proteins; Macrophages, Alveolar; Mice; Monokines; Pulmonary Fibrosis; RNA, Messenger

We evaluated the contribution of interleukin-8 (IL-8) to the pathogenesis of idiopathic pulmonary fibrosis (IPF) by studying bronchoalveolar lavage fluid (BALF) in eight patients with IPF in the chronically progressive phase, five patients with IPF in the subacutely progressive phase, eight patients with sarcoidosis (SAR), and eight control (CTL) subjects. IL-8 levels were not increased in the BALF of the patients with IPF in the chronic phase (11.3 +/- 8.8 pg/ml), nor in that of the SAR patients (13.8 +/- 7.8 pg/ml), whereas they were increased in the BALF of patients with IPF in the subacutely progressive phase (1.93 +/- 1.10 ng/ml). We then investigated extracellular and cell-associated IL-8 in lipopolysaccharide (LPS)-stimulated BALF cells to determine the IL-8-producing potential of alveolar macrophages (AM). Following LPS stimulation of BALF cells from patients with IPF in the chronic phase, both the extracellular IL-8 in culture fluid and the cell-associated IL-8 in AM were increased as compared with those for the CTL subjects (p < 0.05 and p < 0.05, respectively). These results suggest that AM of patients with IPF are primed for IL-8 production. We conclude that IL-8 may play a role in neutrophilic alveolitis, especially during the subacute phase of IPF.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Analysis of Variance; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Chronic Disease; Escherichia coli; Female; Humans; Interleukin-8; Lipopolysaccharides; Macrophage Activation; Macrophages, Alveolar; Male; Middle Aged; Neutrophils; Pulmonary Fibrosis; Sarcoidosis, Pulmonary; Stimulation, Chemical

Fibrosing alveolitis may occur alone (CFA) or in association with systemic sclerosis (FASSc). FASSc was recently shown to have a prognostic advantage over CFA. Because interleukin-8 (IL-8) is likely to be a major determinant of neutrophil alveolitis, we evaluated IL-8 expression in patients with CFA and FASSc and compared it with that in normal individuals and sarcoidosis and systemic sclerosis patients without pulmonary involvement (SSc no FA). IL-8 protein in bronchoalveolar lavage fluid (BALF) was assessed by immunoassay, and IL-8 mRNA expression was assessed using Northern analysis and reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization of lung parenchyma. Compared with normal subjects, IL-8 concentration was significantly greater in both CFA (p < 0.001) and FASSc groups (p < 0.05) but no different in sarcoidosis. The IL-8 concentration in CFA was higher than in FASSc (p < 0.01) and was related to BAL % neutrophils (rs = 0.48, p < 0.01). IL-8 mRNA expression evaluated by Northern analysis was seen only in patients with CFA and FASSc and was related to BAL % neutrophils (rs = 0.63, p < 0.01). We suggest that IL-8 is a key factor in the pathogenesis of fibrosing alveolitis and that the poorer prognosis of CFA compared with FASSc is related to higher levels of IL-8 within the lower respiratory tract.

Topics: Adult; Aged; Blotting, Northern; Bronchoalveolar Lavage Fluid; Female; Humans; Interleukin-8; Lung; Male; Middle Aged; Pulmonary Fibrosis; RNA, Messenger; Scleroderma, Systemic

The potential for interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) to induce neutrophil and mononuclear phagocyte accumulation in the lungs of patients with pulmonary sarcoidosis and idiopathic pulmonary fibrosis (IPF) was investigated. Bronchoalveolar lavage (BAL) fluids from 12 patients with IPF and 15 with sarcoidosis were concentrated by reversed-phase chromatography, and their IL-8 and MCP-1 concentrations assessed by enzyme-linked immunosorbent assay (ELISA), chemotaxis, and enzyme-releasing assays with monocytes and neutrophils. ELISA revealed significantly elevated concentrations of MCP-1 (20.1 ng/mg albumin) in the BAL fluids of patients with pulmonary sarcoidosis and those with IPF (41.8 ng/mg) in comparison to 11 normal individuals (4.24 ng/mg) and 15 patients with chronic bronchitis (CB) (5.16 ng/mg). Similarly, the chemotactic activity for monocytes (MCP-1 equivalent) was strongly increased in patients with sarcoidosis (86.03 ng/mg) as well as in those with IPF (54.47 ng/mg). The chemoattractant activity of normal individuals and CB patients was 7- or 3-fold lower, respectively. Patients with IPF and sarcoidosis also had elevated IL-8 levels (15.5 and 26.0 ng/mg, respectively; normals: 2.14 ng/mg; and CB patients: 4.23 ng/mg) and greater neutrophil chemotaxis (60.25 and 49.68 ng/mg, respectively; normals: 0.35 ng/mg; and CB patients: 11.06 ng/mg). These data suggest that increased levels of both MCP-1 and IL-8 may be characteristic for sarcoidosis or IPF. It appears likely that both of these chemoattractants contribute to the influx of monocytes and neutrophils into the pulmonary alveolus and interstitium in these diseases.

Topics: Adult; Bronchitis; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Chemotactic Factors; Chemotaxis, Leukocyte; Chromatography; Chronic Disease; Cytokines; Enzyme-Linked Immunosorbent Assay; Hexosaminidases; Humans; Interleukin-8; Middle Aged; Monocytes; Neutrophils; Pulmonary Fibrosis; Sarcoidosis, Pulmonary; Sensitivity and Specificity; Severity of Illness Index

Topics: Cell Survival; Cells, Cultured; Culture Media, Conditioned; Fibroblasts; Humans; Interleukin-8; Lung; Neutrophils; Pulmonary Fibrosis; Time Factors

To investigate the pathogenesis of lung injury in Pneumocystic carinii pneumonia and nonspecific interstitial pneumonitis (NIP), common pulmonary complications of human immunodeficiency virus (HIV) infection. The efficacy of corticosteroid therapy in P carinii pneumonia and the observation that bronchoalveolar lavage (BAL) neutrophilia predicts a poor prognosis support the premise that the lung injury of P carinii pneumonia is due to the host's inflammatory response to the infection.. In vitro measurements on previously collected BAL fluid samples.. The Clinical Center of the National Institutes of Health, a research hospital and tertiary care referral center.. Five normal volunteers, 5 asymptomatic HIV-positive patients, 10 HIV-positive patients with NIP (5 asymptomatic and 5 with respiratory symptoms), and 19 HIV-positive patients with P carinii pneumonia.. BAL leukotriene B4 (LTB4), interleukin 8 (IL-8), and phospholipase A2 (PLA2) were measured. IL-8 and PLA2 were elevated in patients with P carinii pneumonia, and IL-8 correlated with BAL fluid absolute neutrophil count. LTB4, IL-8, and PLA2 levels were elevated in patients with NIP; LTB4 and PLA2 levels correlated with absolute neutrophil count, and IL-8 correlated with alveolar-arterial oxygen pressure difference. IL-8 was elevated in the asymptomatic HIV-positive patients, and there was a trend toward elevation of PLA2 in this group.. IL-8 appears to play a role in the pathogenesis of lung injury in P carinii pneumonia and may be the principal neutrophil chemotaxin in this disease; PLA2 may also be involved in the pathogenesis of P carinii pneumonia. Both LTB4 and IL-8 may be involved in the recruitment of neutrophils and subsequent lung injury of NIP. These data suggest that there are varying mechanisms by which inflammatory cells are recruited to the lung in different HIV-related lung diseases.

Topics: Adult; AIDS-Related Opportunistic Infections; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Female; HIV Infections; HIV Seropositivity; Humans; Interleukin-8; Leukotriene B4; Lung Diseases; Male; Middle Aged; Phospholipases A; Phospholipases A2; Pneumonia, Pneumocystis; Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is an immunologically mediated pulmonary disorder in which activated alveolar macrophages (AM) and neutrophils play cardinal roles in the pathogenesis of the inflammatory lung lesion. The factors responsible for the induction and perpetuation of the neutrophilic alveolitis are not known. Recently, a novel cytokine (Interleukin-8) was described that is released by activated mononuclear phagocytes and a variety of other cell types, and it exhibits potent chemotactic activity for polymorphonuclear leukocytes (PMN). Increased expression of IL-8 has been described in other inflammatory disorders characterized by neutrophilic infiltration, including psoriasis, rheumatoid arthritis, and the sepsis syndrome, but no studies have assessed this cytokine in the context of interstitial pulmonary disorders. We have previously shown that normal human AM release IL-8 upon appropriate stimulation, but data assessing the expression of IL-8 by human AM in specific pulmonary disease states are lacking. In this study, we examined the expression of steady-state mRNA for IL-8 by human alveolar macrophages obtained by bronchoalveolar lavage (BAL) from patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis and from healthy volunteers. Because it is known that adherence to plastic culture plates may up-regulate gene expression for IL-8 in the absence of additional stimulation, we extracted mRNA immediately from the cell pellet obtained by BAL rather than using cultured alveolar macrophage monolayers. Northern blot analysis was performed to determine IL-8 mRNA expression. We found that BAL cells from patients with IPF constitutively expressed mRNA for IL-8, and the amount of IL-8 mRNA (as assessed by laser densitometry) correlated with the percent of neutrophils on BAL.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Bronchoalveolar Lavage Fluid; Female; Gene Expression; Humans; Interleukin-8; Lung Diseases; Macrophages, Alveolar; Male; Middle Aged; Neutrophils; Pulmonary Fibrosis; RNA, Messenger; Sarcoidosis

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.

Topics: Actins; Adult; Base Sequence; Female; Gene Expression; Humans; Interleukin-8; Macrophages, Alveolar; Male; Middle Aged; Molecular Sequence Data; Neutrophils; Polymerase Chain Reaction; Pulmonary Fibrosis; RNA, Messenger

To clarify the localization and mechanism of neutrophil infiltration in the lower respiratory tract, we measured neutrophil number, neutrophil chemotactic factor (NCF) activity and content of C5 in bronchial lavage (BL) fluid and bronchoalveolar lavage (BAL) fluid. Numbers of neutrophils, NCF activity and C5 content were higher in the BL fluid from normal volunteers (NV) and control patients (CP) than those in the BAL fluid from the same subjects. The NCF activity in the BL fluid was inhibited approximately 40% by anti-C5 antiserum, and correlated with C5 content in the BL fluid. In the BAL fluids of patients with chronic airway diseases (CAD) and patients with idiopathic interstitial pneumonia (IIP), neutrophil number, NCF activity and C5 content were increased compared to those in BAL fluid from NV or CP. These results indicated that neutrophils are predominant in the bronchial region compared to the alveolar region, and that C5-derived NCF play important roles in the accumulation of neutrophils in the bronchial region. Also C5-derived NCF are thought to be related to, at least, a part of the neutrophil infiltration in the respiratory tract of patients with CAD and IIP.

Topics: Adult; Aged; Bronchi; Bronchoalveolar Lavage Fluid; Complement C5; Humans; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Neutrophils; Pulmonary Alveoli; Pulmonary Fibrosis