IL-9 and IL-9 receptor expression in lymphocytes from bronchoalveolar lavage fluid of patients with interstitial lung disease

IntroductionIL-9, mainly produced by T helper 9 (Th9) cells, promotes allergic airway inflammation and remodeling through the interaction with its receptor (IL-9R). Th9 cells and IL-9 have also been implicated in tissue fibrosis and autoimmunity pathways. However, the role of IL-9/IL-9R in the pathogenesis of interstitial lung disease (ILD) is unknown.AimTo evaluate IL-9/IL-9R expression in bronchoalveolar lavage fluid (BALF) lymphocytes of patients with various ILDs.MethodsConsecutive patients with ILD, who underwent BAL for diagnostic purposes, were studied. As control group, consecutive patients without evidence of ILD were included. Immunocytochemical staining of BALF lymphocytes for IL-9 and IL-9R was performed and evaluated by two independent readers.Results45 patients, of them 8 had idiopathic pulmonary fibrosis (IPF), 12 nonspecific interstitial pneumonia (NSIP), 10 sarcoidosis, 9 hypersensitivity pneumonitis (HP), 6 cryptogenic organizing pneumonia (COP), and 24 controls were studied. In the ILD group, the highest BALF lymphocyte count was seen in HP followed by NSIP, COP, sarcoidosis, and IPF (p < 0.05 for HP vs IPF). The highest percentages of IL-9 and IL-9R positive lymphocytes were seen in COP. Conversely, NSIP showed the lowest rate of IL-9, and sarcoidosis the lowest rate of IL-9R positive lymphocytes. Only in NSIP, a direct correlation between IL and 9 and IL-9R positive lymphocytes was seen (r = 0.639, p = 0.025).ConclusionBALF lymphocytes IL-9 and IL-9R expression differs between various ILDs and could reflect different pathogenetic mechanisms.     

Increased IL-6 and IL-8 in bronchoalveolar lavage fluids (BALF) from patients with sarcoidosis: correlation with the clinical parameters

A variety of cytokines have been implicated in the pathogenesis of pulmonary sarcoidosis, but the exact roles of IL-6 and IL-8 are not yet clear. We studied these cytokine levels in BALF from patients with pulmonary sarcoidosis, idiopathic pulmonary fibrosis (IPF), systemic screlosis (SSc) with interstitial lung disease and control subjects. IL-6 and IL-8 levels were significantly elevated in sarcoidosis, IPF and SSc with interstitial lung disease compared with control subjects. Subjects with sarcoidosis had significantly increased levels of both cytokines compared with controls when the cytokine values were corrected by the total albumin content and the two cytokine levels correlated with each other (r=0.876). BALF IL-6 levels correlated with percent lymphocytes and percent CD3⁺ cells. Moreover, when sarcoidosis patients were divided into three groups, those who needed steroid therapy or had progressive disease showed increased cytokine levels in BALF over stable or improved patients. These observations suggest that locally derived IL-6 and IL-8 were increased in sarcoidosis and correlated with activity of this granulomatous lung disease.     

BAL in the diagnosis of smoking-related interstitial lung diseases: review of literature and analysis of our experience

The group of interstitial lung diseases (ILDs) is formed by respiratory tract disorders, whose aetiology is unknown in the majority of cases, the clinical course differs and the prognosis is generally serious. Some of the ILDs have a potential relation to tobacco smoking and are known as smoking-related ILDs (sr-ILD). Bronchoalveolar lavage fluid (BALF) examination is one of the initial procedures in the diagnosis of ILD. Despite the fact that histological confirmation is the gold standard in ILD diagnosis in many studies, the number of reported biopsies was low. In this review we present the results of BALF examinations of patients with sr-ILD and discuss their value in the differential diagnosis with other types of ILD. An extremely high total cell count (about 50 x 10(6) cells) with significant predominance of pigmented alveolar macrophages is a characteristic pattern of BALF in sr-ILD. The greatest challenge in BALF cytology interpretation is to distinguish sr-ILD and idiopathic pulmonary fibrosis (IPF). IPF is characterised by an elevated proportion and absolute count of lymphocytes and neutrophils; in addition, BALF lymphocytosis is higher in non-specific interstitial pneumonia than in usual interstitial pneumonia (UIP). The population of alveolar macrophage of patients with sr-ILD differs markedly from the foamy and vacuolated cells that predominate in IPF/UIP. Thus, the absence of pigmented cells rather excludes sr-ILD and indicates other types of ILD. To summarise, the place of BALF in the diagnosis of sr-ILD seems to be established.     

MRP14 is elevated in the bronchoalveolar lavage fluid of fibrosing interstitial lung diseases

Pulmonary fibrosis is defined by an overgrowth of fibroblasts and extracellular matrix deposition, and results in respiratory dysfunction that is often fatal. It is the end stage in many chronic inflammatory interstitial lung diseases (ILD) such as sarcoidosis and idiopathic pulmonary fibrosis (IPF). The myeloid‐related proteins (MRPs) belong to the S100 family of calcium‐binding proteins and are highly expressed by neutrophils, macrophages and epithelial cells during chronic inflammation. MRP14 stimulates fibroblast proliferation in vitro and is expressed in granulomas from sarcoidosis patients. We hypothesized that MRP14 may be a biomarker for fibrotic interstitial lung diseases. The objective of this study was to investigate whether levels of MRP14 in the bronchoalveolar lavage fluid (BALF) of patients with sarcoidosis and IPF correlate with clinical parameters. We used an enzyme‐linked immunosorbent assay (ELISA) to measure MRP14 in BALF of 74 sarcoidosis patients, 54 IPF patients and 19 controls. Mean BALF levels of MRP14 were elevated significantly in IPF (P < 0·001) and sarcoidosis (P < 0·05) patients compared to controls. MRP14 levels were associated linearly with sarcoidosis disease severity based on chest radiographic stage. Moreover, BALF MRP14 levels were correlated inversely with diffusion capacity and forced vital capacity in sarcoidosis patients. In IPF patients, a correlation with BALF neutrophil percentage was found. In conclusion, BALF MRP14 levels are elevated in IPF and sarcoidosis and are associated with disease severity in sarcoidosis. The results support the need for further studies into the role of MRP14 in the pathogenesis of lung fibrosis.     

Expression of mucosa-related integrin alphaEbeta7 on alveolar T cells in interstitial lung diseases.

The expression of alphaEbeta7 integrin has been related to the selective retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. To identify potential disease-associated alphaEbeta7 expression patterns on cells accounting for lymphocytic alveolitis in interstitial lung disease (ILD), alphaE expression on CD4+ and CD8+ T cell subsets was evaluated by dual-colour flow cytometry in peripheral blood and bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF; n = 18), hypersensitivity pneumonitis (HP; n = 20) and sarcoidosis (n = 44) in comparison with healthy controls (n = 15). In both healthy individuals and all patient groups the proportion of alphaE-bearing T cells in peripheral blood was < 2%, whereas the vast majority of alveolar CD8+ T cells consistently co-expressed alphaE. Absolute alveolar CD8+alphaE+ cell numbers/ml were up to 30-fold increased in HP patients. Proportions of alphaE-bearing CD4+ cells in BALF were significantly elevated in IPF (74.0 +/- 2.7%) and HP (70.0 +/- 2.4%) compared with normals (30.0 +/- 1.8%) (mean +/- s.e.m.; P < 0.01). In sarcoidosis, the alphaE expression on BALF CD4+ cells displayed subgroup dependency: proportions significantly lower than normal were noted in chest radiographic stage I (14.3 +/- 1.5%), but increased proportions in stages II (50.0 +/- 3.8%) and III (64.0 +/- 4.8%). Correlations between common markers of T cell activation or BALF transforming growth factor-beta (TGF-beta ) bioactivity and alphaE expression were not noted. We conclude that the vast majority of alveolar CD8+ T cells consistently express alphaEbeta7 and that distinct patterns of alphaEbeta7 expression on alveolar CD4+ lymphocytes in sarcoidosis are related to the diverse manifestations of the sarcoid inflammatory process in the lung.     

Suppressive activity of alveolar macrophages and blood monocytes from interstitial lung diseases: role of released soluble factors

Two groups of patients suffering from interstitial lung diseases (ILD) namely sarcoidosis (SA) and idiopathic pulmonary fibrosis (IPF) were investigated for alveolar macrophages (AM), secretion of prostaglandin E2 (PGE2) and interleukin 1 (IL-1), together with superoxide anion (O2-) production. Peripheral blood monocytes (PBMO) of the same patients were examined concomitantly for suppressive activity. Consistent with previous results, AM obtained by bronchoalveolar lavage (BAL) from ILD patients markedly suppressed the effects of PHA stimulation of autologous peripheral blood lymphocytes (APL): 61.8 +/- 9.7% suppressive activity compared to 15.5 +/- 15.4% in the control group (CO) P less than 0.001. The AM suppressive activity was correlated with an increase in PGE2 secretion: 3.861 +/- 2.194 ng/10(5) cells/ml in the IPF group, but not in the sarcoid group: 0.217 +/- 0.116 ng/10(5) cells/ml (P less than 0.001 between them). On the other hand, IL-1 secretion by AM was greatly increased in sarcoid patients (308 +/- 196 U/ml) but was within the normal limits in IPF (27.3 +/- 28.8 U/ml, P less than 0.01 between them). Therefore, an inverse correlation was found between degree of PGE2 secretion and IL-1 release by AM in ILD. O2-production by AM was markedly increased in all ILD patients but this mechanism is apparently not involved in suppressive activity. PBMO originating from ILD patients were less suppressive than the corresponding AM.     

Characterization of p40 and IL-10 in the BALF of patients with pulmonary sarcoidosis.

This study investigated cytokine protein levels (interleukin-12 p70 [IL-12p70], p40, and IL-10) in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis (n = 59), healthy control subjects (n = 17), and patients with idiopathic pulmonary fibrosis (IPF) (n = 30). The relationship between cytokine levels and clinical course of sarcoidosis was also examined. Overall, p40 was far more abundant than IL-12p70. p40 levels (pg/ml, mean +/- SEM) were significantly higher in the BALF from patients with sarcoidosis (2.97 +/- 3.69) than in IPF patients (0.83 +/- 1.57) and healthy subjects (0.78 +/- 1.00). Size exclusion chromatography indicated that p40 detected in BALF from sarcoidosis patients corresponded to p40 monomers or (p40)(2) homodimers. Further, p40 levels were associated with (paralleled) the clinical course of sarcoidosis, with the highest levels detected in BALF from patients with persistent disease. Higher p40 levels were also found in the BALF from sarcoid patients who required corticosteroid treatment compared with patients with spontaneous regression (3.51 +/- 3.83 vs. 2.01 +/- 3.43, p = 0.03). IL-10 concentrations paralleled p40 changes. No similar association was found for IL-12p70 levels. In conclusion, this report shows that the BALF from patients with sarcoidosis contains elevated levels of p40, (p40)(2), and IL-10 protein but not of IL-12p70. The present data also suggest that BALF p40 concentrations may be indicative of the sarcoidosis clinical course.     

Heat Stress Protects Against Lung Injury in the Neutropenic,Endotoxemic Rat

The objective of this study is to determine if heat stress prior to endotoxemia diminishes cardiopulmonary dysfunction by attenuating the cytokine inflammatory response. Rats were assigned to either: 1) neutropenia; 2) heat; 3) neutropenia, LPS; or 4) heat, neutropenia, LPS. Heart rate, blood gases, and blood, lung lavage, and lung mRNA for tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and macrophage inflammatory protein (MIP)-2 were measured. Heat given before LPS resulted in a similar A-a O₂ gradient as the heat-alone and neutropenic groups (8 ± 8 versus 8 ± 7 versus 4 ± 3 mm Hg) and a lower A-a O₂ gradient when compared to the neutropenic, LPS rats (8 ± 8 versus 22 ± 8 mm Hg, p < 0.003). Blood, lung lavage, and lung mRNA for TNF-α, IL-1β, and MIP-2 were similar in the LPS rats regardless of heat. Heart rate was similar in both LPS groups but higher than non-LPS groups. Heat pretreatment attenuates lung injury in the neutropenic, endotoxemic rat but not by decreasing TNF-α, IL-1β, or MIP-2 in the lung. Heat prior to LPS did not prevent cardiac dysfunction in neutropenic rats.     

Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis

Cha S‐I, Chang C S, Kim E K, Lee J W, Matthay M A, Golden J A, Elicker B M, Jones K, Collard H R & Wolters P J (2012) Histopathology  61, 98–106 Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis Aims: The relationship of mast cells to the pathogenesis of lung fibrosis remains undefined despite recognition of their presence in the lungs of patients with pulmonary fibrosis. This study was performed to characterize the relationship of mast cells to fibrotic lung diseases. Methods and results: Lung tissues from patients with idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP), systemic sclerosis (SSc)‐related interstitial lung disease (ILD) and normal individuals were subjected to chymase immunostaining and the mast cell density quantified. Eosinophils were quantified by immunostaining for eosinophil peroxidase. Changes in lung function were correlated with mast cell density. Lung tissue obtained from IPF patients had a higher density of chymase‐immunoreactive mast cells than that from patients with HP, SSc‐related ILD or normal lungs. IPF lung tissue had a higher density of eosinophils than normal lung. There was no correlation between mast cell density and eosinophil density in IPF lung. IPF patients with high mast cell density had a slower rate of decline in forced vital capacity (FVC) than IPF patients with low mast cell density. Conclusions: Mast cell density in IPF lungs is higher than in other fibrotic lung diseases and normal lungs. Increased mast cell density in IPF may predict slower disease progression.     

Measurement of small quantities of alpha 2-macroglobulin in bronchoalveolar lavage fluid by enzyme-labelled immunoassay, and its clinical implication in pulmonary disease

We established an enzyme labelled immunoassay for the determination of alpha 2 macroglobulin (alpha 2M). The assay range was from 2 to 140 ng/ml and the within-assay coefficient of variation (CV) were 5.2% at 31.2 ng/ml and 6.4% at 62.5 ng/ml. Between-day CV ranged from 6.9% to 15.4%. Using this method, alpha 2 M was determined in the bronchoalveolar lavage fluid (BALF) from patients with interstitial lung diseases. Those diseases were active and inactive sarcoidosis, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis (IPF, including collagen disease). We divided the IPF patients into two groups, 'acute type' and 'chronic type', judging from the prognosis. alpha 2 M/Albumin ratio in BALF in the active sarcoidosis and acute type IPF groups is significantly higher than that in the inactive sarcoidosis and chronic type IPF. These findings suggest that alpha 2 M in BALF can be a sensitive marker of the interstitial lung disease.     

3Development of an in vitro model for human embryo implantation and progesterone regulation

Aim:  Develop an in vitro 3D-model for human embryo implantation on receptive endometrial construct.
Material and Methods:  Three-dimensional in vitro endometrial construct (n=12) was developed by culturing isolated human endometrial stromal cells in collagen matrix overlaid with epithelial cells. After priming hormonally, human blastocysts were placed and cultured in alpha-medium. Attachment of embryo was confirmed using cytokeratin-7 and expression of endometrial receptivity markers using immunohistochemistry. Antiprogestin mifepristone was used to test implantation and receptivity.
Results:  Embryos attached to receptive endometrial construct . Epithelial and stromal cells of endometrial construct expressed ER-α, ER-β, PR-(A+B), PR-B, VEGF, LIF, IL-1beta and COX-2. Epithelial cells expressed AR, integrinα_Vβ₃ and MUC1. Mifepristone inhibited blastocyst attachment, up-regulated epithelial ER-β, PR-B; down regulated stromal VEGF, MUC1 and integrin α_Vβ₃ as observed in vivo .
Conclusion:  An in vitro human embryo implantation model, regulated by progesterone was developed and tested. This could be further used to understand molecular basis of human embryo implantation .     

T cell activation profiles in different granulomatous interstitial lung diseases – a role for CD8+CD28null cells?

Lymphocytes play a crucial role in lung inflammation. Different interstitial lung diseases may show distinct lymphocyte activation profiles. The aim of this study was to examine the expression of a variety of activation markers on T lymphocyte subsets from blood and bronchoalveolar lavage fluid (BALF) of patients with different granulomatous interstitial lung diseases and healthy controls. Bronchoalveolar lavage cells and blood cells from 23 sarcoidosis patients, seven patients with hypersensitivity pneumonitis and 24 healthy controls were analysed. Lymphocyte activation status was determined by flow cytometry. Lymphocytes were stained with antibodies against CD3, CD4, CD8, CD25, CD28, CD69, very late antigen‐1 (VLA)‐1, VLA‐4 and human leucocyte antigen D‐related (HLA‐DR). In general, CD28, CD69 and VLA‐1 expression on BALF CD4⁺ lymphocytes and HLA‐DR expression on BALF CD8⁺ lymphocytes was different in patients with hypersensitivity pneumonitis and sarcoidosis patients with parenchymal involvement. This BALF lymphocyte phenotype correlated with carbon monoxide diffusing lung capacity (Dlco) values across interstitial lung diseases (ILD) (r² = 0·48, P = 0·0002). In sarcoidosis patients, CD8⁺CD28^null blood lymphocytes correlated with lower Dlco values (r = ?0·66, P = 0·004), chronic BALF lymphocyte activation phenotype (r² = 0·65, P < 0·0001), radiographic staging (stage I versus stage II and higher, P = 0·006) and with the need for corticosteroid treatment (P = 0·001). Higher expression of CD69, VLA‐1 and HLA‐DR and lower expression of CD28 on BALF lymphocytes suggests prolonged stimulation and chronic lymphocyte activation in patients with ILD. In sarcoidosis, blood CD8⁺CD28^null cells might be a new biomarker for disease severity but needs further investigation.     

Enhanced expression of interleukin-18 and its receptor in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is a major interstitial lung disease (ILD). Recently, we established a new mouse model for ILD in which daily administration of interleukin (IL)-18 with IL-2 induces lethal lung injury, suggesting that IL-18 is involved in the pathogenesis of ILD. Here, utilizing immunohistochemistry, we have analyzed IL-18 and IL-18 receptor (IL-18R) alpha expression in the lungs of 18 patients with IPF/UIP and 13 control subjects by using monoclonal anti-IL-18 antibodies and a new monoclonal antibody for IL-18Ralpha (H44). IL-18 was expressed in bronchoalveolar epithelium, alveolar macrophages, and the endothelium of small vessels in control subjects, and was abundantly expressed in the majority of pulmonary cells in patients with IPF. IL-18Ralpha was expressed in bronchoalveolar epithelium and alveolar macrophages in control subjects, and was strongly expressed in interstitial cells in patients with IPF, especially in the fibroblastic foci (FF). Interestingly, IL-18Ralpha expression was only weakly observed in areas showing established fibrosis. Semiquantitative analysis revealed that the histologic FF score was significantly correlated with the IL-18Ralpha expression level in FF lesions. Moreover, IL-18 levels in the serum and bronchoalveolar lavage fluid of patients with IPF were significantly higher than those in control subjects. Our findings suggest IL-18 and IL-18R are involved in the pathogenesis of IPF/UIP.     

Effect of an Extract Based on the Medicinal Mushroom Agaricus blazei Murill on Release of Cytokines, Chemokines and Leukocyte Growth Factors in Human Blood Ex Vivo and In Vivo

An immunostimulatory extract based on the medicinal mushroom Agaricus blazei Murill (AbM) has been shown to stimulate mononuclear phagocytes in vitro to produce pro-inflammatory cytokines, and to protect against lethal peritonitis in mice. The present aim was to study the effect of AbM on release of several cytokines in human whole blood both after stimulation ex vivo and in vivo after oral intake over several days in healthy volunteers. The 17 signal substances examined were; T helper 1 (Th1) cytokines [interleukin (IL)-2, interferon (IFN)-γ and IL-12], T helper 2 cytokines (IL-4, IL-5 and IL-13), pleiotropic (IL-7, IL-17), pro-inflammatory [IL-1β, IL-6, tumour necrosis factor (TNF)-α (mainly produced by Th1 cells)] – and anti-inflammatory (IL-10) cytokines, chemokines [IL-8, macrophage inhibitory protein (MIP)-1β and monocyte chemoattractant protein (MCP)-1] and leukocyte growth factors [granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor]. After stimulation of whole blood ex vivo with 0.5–5.0% of a mushroom extract, AndoSan™ mainly containing AbM , there was a dose-dependent increase in all the cytokines studied, ranging from two to 399-fold (TNF-α). However, in vivo in the eight volunteers who completed the daily intake (60 ml) of this AbM extract for 12 days, a significant reduction was observed in levels of IL-1β (97%), TNF-α (84%), IL-17 (50%) and IL-2 (46%). Although not significant, there was a trend towards reduced levels for IL-8, IFN-γ and G-CSF, whilst those of the remaining nine cytokines tested, were unaltered. The discrepant results on cytokine release ex vivo and in vivo may partly be explained by the antioxidant activity of AbM in vivo and limited absorption of its large, complex and bioactive β-glucans across the intestinal mucosa to the reticuloendothelial system and blood.     

Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1β in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown aetiology. Interleukin (IL)-1β plays an important role in inflammation and has been associated with fibrotic remodelling. We investigated the balance between IL-1β and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) and serum as well as the influence of genetic variability in the IL1B and IL1RN gene on disease susceptibility and cytokine levels. In 77 IPF patients and 349 healthy controls, single nucleotide polymorphisms (SNPs) in the IL1RN and IL1B genes were determined. Serum and BALF IL-1Ra and IL-1β levels were measured using a multiplex suspension bead array system and were correlated with genotypes. Both in serum and BALF a significantly decreased IL-1Ra/IL-1β ratio was found in IPF patients compared to healthy controls. In the IL1RN gene, one SNP was associated with both the susceptibility to IPF and reduced IL-1Ra/IL-1β ratios in BALF. Our results show that genetic variability in the IL1RN gene may play a role in the pathogenesis of IPF and that this role may be more important than thought until recently. The imbalance between IL-1Ra and IL-1β might contribute to a proinflammatory and pro-fibrotic environment in their lungs.     

Interstitielle Lungenerkrankungen

Interstitial lung diseases (ILDs) comprise a number of rare entities with an estimated incidence of 10–25 per 100,000 inhabitants but the incidence greatly increases beyond the age of 65 years. The prognosis depends on the underlying cause. The fibrotic disorders show a set of radiological and histopathological patterns that are distinct but not entirely specific. In the absence of a clear clinical picture and consistent high resolution computed tomography (HRCT) findings, patients are advised to undergo surgical lung biopsies from two or three lung lobes (or transbronchial biopsies) to determine the histopathological pattern. The ILDs are differentiated into disorders of known causes (e.g. collagen vascular disease, drug-related), idiopathic interstitial pneumonia (IIP), granulomatous ILDs (e.g. sarcoidosis) and other forms of ILD (e.g. Langerhans’ cell histiocytosis). The IIPs encompass idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, cryptogen organizing pneumonia, lymphocytic interstitial pneumonia and acute interstitial pneumonia. Additionally, a category of unclassified interstitial pneumonia exists. The pathologist has to recognize and address the histopathological pattern. In a multidisciplinary discussion the disorder is allocated to a clinicopathological entity and the histopathological pattern plays a major role in the classification of the entity. Recognition of the underlying pattern and the respective histopathological differential diagnoses is important as the therapy varies depending on the cause and ranges from elimination of the stimulus (if possible) to antifibrotic drug therapy up to preparation for lung transplantation.     

Elevated matrilysin levels in bronchoalveolar lavage fluid do not distinguish idiopathic pulmonary fibrosis from other interstitial lung diseases

Microarray studies have shown that matrilysin or matrix metalloproteinase (MMP)-7 is highly upregulated in the lungs of patients with idiopathic pulmonary fibrosis (IPF), but MMP-7 protein expression has not been systematically compared between IPF and other interstitial lung diseases. MMP-7 levels in bronchoalveolar lavage fluid (BALF) were compared to corresponding samples from nonspecific interstitial pneumonia (NSIP), sarcoidosis, and healthy controls. MMP-7 levels in the BALF were determined by ELISA and localization of MMP-7 in the lung tissue by immunohistochemistry. MMP-7 was similarly elevated in the BALF of all these disorders compared to healthy controls (p=0.007). Even control subjects with prolonged cough displayed a tendency towards elevated MMP-7 expression. There was a negative correlation between BALF MMP-7 levels and forced expiratory vital capacity (r=-0.348, p=0.02, n=42). In IPF lung, MMP-7 immunoreactivity appeared predominantly in the fibrotic parenchyma and arterial wall. In sarcoidosis and NSIP, prominent MMP-7 immunoreactivity was found in areas of inflammation. These results demonstrate that elevated BALF MMP-7 is not restricted to IPF alone but is also observed in other interstitial lung diseases and cannot be used as a differential diagnostic marker for IPF.     

Maternal Circulating TNF-α Levels are Highly Correlated with IL-10 Levels, but not IL-6 and IL-8 Levels, in Women with Pre-Eclampsia

Problem  Several lines of evidence have shown that maternal cytokine levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and IL-10 were altered in women with pre-eclampsia (PE) compared to those from normal pregnancies. In this study, we determined whether these cytokine levels are correlated before and after delivery in patients with PE.
Method of study  Venous blood was obtained from 50 women diagnosed with severe PE at the time of admission and 24 hr after delivery. Plasma concentrations for TNF-α, IL-6, IL-8, and IL-10 were measured by ELISA.
Results  There were no statistical differences for maternal levels of TNF-α, IL-6, IL-8, and IL-10 before and 24 hr postpartum. TNF-α and IL-10, but not IL-6 and IL-8, levels were significantly correlated before and 24 hr after delivery: TNF-α: y  = 19.963 + 0.953* x ; r ² = 0.924; IL-10: y  = 10.521 + 1.113* x ; r ² = 0.984, P  < 0.001, respectively. Furthermore, TNF-α levels were correlated with IL-10 levels, but not with IL-6 and IL-8 levels.
Conclusion  The correlation patterns of TNF-α with IL-10 and TNF-α with IL-6 and IL-8 suggest disparity in functional regulations between these cytokines in maternal circulation in PE.