Biomedical subjects

V L Kinnula

Publications and source records attributed to V L Kinnula.

At least 19 recordsLinked to original sources

PubMed2006

8-Isoprostane as a marker of oxidative stress in nonsymptomatic cigarette smokers and COPD.

8-Isoprostane is a potential in vivo marker for oxidant burden, but its usefulness in induced sputum of smokers and chronic obstructive pulmonary disease (COPD) has not been investigated. The current study investigated 58 subjects comprising 11 never-smokers, 11 ex-smokers, 13 healthy current smokers and 23 COPD with stage 0-III disease (according to the Global Initiative for Chronic Obstructive Lung Disease criteria). 8-Isoprostane was determined from induced sputum by enzyme immunoassay. Sputum 8-isoprostane levels were similar in the never-smokers and ex-smokers, but were elevated in the healthy smokers compared with nonsmokers, and in those with stage I-III COPD. Sputum 8-isoprostane levels could not differentiate nonsymptomatic smokers from those with Stage 0 COPD. There was a correlation between sputum 8-isoprostane level and lung function parameters (forced expiratory volume in one second/forced vital capacity and sputum neutrophils. In conclusion, sputum 8-isoprostane levels correlate with the severity of chronic obstructive pulmonary disease. However, they do not appear to differentiate healthy smokers from those who are at risk of developing chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease stage 0).

Biomarkers↗

PubMed2006

Airway neutrophilia in COPD is not associated with increased neutrophil survival.

Neutrophilic airway inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD) and correlates with disease severity. The mechanisms that determine the extent of neutrophilia could involve increased influx or prolonged survival of neutrophils. The aim of the study was to assess whether neutrophil pro-survival mechanisms are increased in the airways of subjects with COPD owing to the presence of anti-apoptotic factors in the bronchial lining fluid. Induced sputum samples were collected from 20 subjects with stable COPD, 14 healthy smokers and 14 healthy controls. Quantification of apoptotic neutrophils was based on typical morphological cell changes. Anti-apoptotic, pro-survival activity in the sputum was studied by culturing peripheral blood neutrophils with the fluid phase of induced sputum. Apoptosis was assessed both by morphology and flow cytometry using Annexin V/7-aminoactinomycin D staining. COPD patients and healthy smokers had significantly higher percentages of sputum neutrophils than healthy controls. However, there were no significant differences between the three subject groups in either the proportion of apoptotic neutrophils in sputum or the in vitro anti-apoptotic activity detected in the sputum fluid phase. In conclusion, prolonged survival of neutrophils in sputum is not a feature of chronic obstructive pulmonary disease and cannot explain the increased numbers of airway neutrophils in this disease.

Adult↗

PubMed2006

Relationship between histopathological features and the course of idiopathic pulmonary fibrosis/usual interstitial pneumonia.

BACKGROUND: Fibroblastic focus (FF) is the typical histopathological feature of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). A study was undertaken to analyse FF at diagnosis, to analyse the histopathological findings at necropsy, and to examine their association with the course of the disease. METHODS: A retrospective study was made of 76 UIP cases collected over a period of 30 years from one university hospital; 64 had idiopathic IPF. The surface area of one slide of each lung biopsy specimen was defined by image analysis and the total number of FF was quantified. The histological features of necroscopic lung samples were re-analysed in 11 cases. Clinical follow up information was obtained from the registers. RESULTS: Patients with < or =50 FF/cm(2) (n = 34) in the lung biopsy specimen had a median survival of 89 months (95% CI 38 to 140) compared with 49 months (95% CI 36 to 62) in those with >50 FF/cm(2) (n = 42, p = 0.0358). Diffuse alveolar damage (DAD) was detected in 10 necropsy samples and almost prevented the histopathological confirmation of UIP in six cases. Accumulation of neutrophils occurred in nine cases. There was no association between FF at diagnosis and DAD at necropsy, or between FF and exacerbation of the disease before death. CONCLUSIONS: The number of FF in lung samples before death is associated with poor survival but not with DAD, which is a common feature in necropsy specimens of patients with UIP. FF cannot predict an acute exacerbation of IPF.

Adult↗

PubMed2006

Extracellular superoxide dismutase has a highly specific localization in idiopathic pulmonary fibrosis/usual interstitial pneumonia.

AIMS: Recent studies suggest the importance of oxidant stress in the progression of pulmonary fibrosis. The aim of this study was to investigate extracellular superoxide dismutase (ECSOD), the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven idiopathic pulmonary fibrosis (IPF) related to usual interstitial pneumonia (UIP). METHODS AND RESULTS: Fibrotic areas and fibroblastic foci in UIP lungs were notable for absence of ECSOD by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of ECSOD in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense ECSOD positivity in UIP was the interstitial mast cell. In order to investigate the mechanism for ECSOD depletion in fibrotic areas, alveolar epithelial cells were exposed to tumour necrosis factor-alpha and transforming growth factor (TGF)-beta1; TGF-beta suggested a trend towards decreased synthesis. Patients with UIP were also assessed to determine whether this disease is associated with a naturally occurring mutation in ECSOD (Arg213Gly) which leads to a loss of tissue binding of ECSOD. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 UIP patients and 61 control subjects. CONCLUSION: Overall, consistent with several other antioxidant enzymes, ECSOD is very low in fibrotic areas of UIP, which may further increase the oxidant burden in this disease.

Adult↗

PubMed2006

Oxidative/nitrosative stress and peroxiredoxin 2 are associated with grade and prognosis of human renal carcinoma.

Peroxiredoxins (Prxs) 1-6 were assessed in 138 renal cell carcinomas (RCC) using immunohistochemistry and selected samples by Western blotting analysis. Oxidative/nitrosative damage was evaluated using nitrotyrosine immunoreactivity. The expressions of Prxs were correlated with tumor grade and survival and nitrotyrosine reactivity. Non-malignant kidney tubular cells showed positivity with variable intensity for all six Prxs. In RCCs, most cases were positive for Prxs 1 and 2, while only 15-20% of tumors showed expression for Prxs 3 and 4. Prx 2 was associated with tumors of a lower grade (p=0.009) and with a lower frequency of distant metastases (p=0.046). Patients with tumors expressing Prx2 had better prognosis (p=0.027). Instead, nitrotyrosine was significantly associated with high grade tumors (p=0.001). Compared with the non-malignant kidney tubular cells, low Prx expression in the tumor cells can make them more susceptible to oxidative damage. Prx 2 was more abundantly expressed in low grade tumors, suggesting that this protein could play a role in preventing the development of oxidative damage, which in turn can lead to the activation of pathways leading to aggressive tumors.

Adult↗

PubMed2005

Focus on antioxidant enzymes and antioxidant strategies in smoking related airway diseases.

Cigarette smoke causes significant oxidant stress which is further enhanced by recruitment and activation of inflammatory cells to the lung. Polymorphisms in some detoxification enzymes are thought to increase the risk of developing chronic obstructive pulmonary disease (COPD), but the ultimate role of genetic variability in antioxidant and/or detoxification enzymes in COPD remains obscure. Some antioxidant enzymes are inducted, but the extent of induction is insufficient to protect the lung/alveolar epithelium against cigarette smoke. Exogenous antioxidants such as vitamins do not seem to protect against cigarette smoke related lung injury. Glutathione related synthetic drugs such as N-acetylcysteine have shown some benefits, but they may have pro-oxidant side effects. Synthetic compounds with superoxide dismutase and catalase activities have shown promising results in animal models against a variety of oxidant exposures including cigarette smoke in the lung. These results are in agreement with studies highlighting the importance of alveolar antioxidant protection mechanisms in oxidant stress and their inducibility. These new drugs need to be tested in cigarette smoking related lung injury/inflammation since inflammation/oxidant stress can continue after discontinuation of smoking.

Antioxidants↗

PubMed2004

Two functional variants of the superoxide dismutase genes in Finnish families with asthma.

BACKGROUND: Functional polymorphisms in the genes encoding superoxide dismutases (SOD)-that is, superoxide scavenging antioxidant enzymes-may play an important role in the development of inflammatory airway diseases such as asthma. METHODS: The allele frequencies of two missense polymorphisms of SOD genes (Ala16Val in MnSOD (SOD2) and Arg213Gly in ECSOD (SOD3)) were investigated in Finnish patients with asthma and compared with family based controls. Both variants have been shown to be functionally interesting in the lung. The polymorphism at the exon-intron 3 boundary of a third SOD, CuZnSOD (SOD1), was also included in the analysis. RESULTS: None of the SOD genetic variants studied appeared to be major genetic regulators in the development of asthma. We could exclude all models of inheritance that increased the risk of asthma more than 1.2 fold for MnSOD*Val (frequency of allele 0.74 in the population) and more than 6.6 fold for ECSOD*Gly213 (frequency of allele 0.03 in the population) compared with non-carriers. For the intronic polymorphism in CuZnSOD, a relative risk of more than 3.3 (frequency of allele 0.10 in the population) could be excluded. CONCLUSIONS: It is highly unlikely that the functionally important genetic variants Ala16Val and Arg213Gly of SODs play a major role in the genetic susceptibility of asthma.

Adolescent↗

PubMed2004

Manganese superoxide dismutase is increased in the airways of smokers' lungs.

Oxidant stress is a key mechanism for smoking-induced chronic obstructive pulmonary disease (COPD). Smoking has been shown to upregulate several antioxidant enzymes, with potential effects on the prevention of the disease and/or its progression. Superoxide dismutases (SOD)s are the only enzymes capable of consuming superoxide radicals. The purpose of the present study was to investigate SODs in the lungs of nonsmokers, smokers and COPD patients. Manganese superoxide dismutase (MnSOD), copper zinc SOD (CuZnSOD), and extracellular SOD (ECSOD), were investigated by immunohistochemistry in the airways of 13 nonsmokers, 20 smokers and 22 COPD patients with mild-to-moderate disease. Lung tissue homogenates of three nonsmokers and four smokers were used for Western blot and enzyme activity analysis. The expression of MnSOD was higher in the central bronchial epithelium of smokers with COPD and in the alveolar epithelium of smokers without or with COPD than innonsmokers. Lung MnSOD immunoreactivity, evaluated by Western blotting and specific activity, were 33% and 51% higher, respectively, in smokers than in nonsmokers. No major changes could be observed in lung CuZnSOD or ECSOD immunoreactivities. Manganese superoxide dismutase is elevated in the alveolar epithelium of cigarette smokers, probably due to the increased oxidant burden in smokers' lungs.

Aged↗

PubMed2003

Over-expression of tenascin-C in malignant pleural mesothelioma.

AIMS: Tenascin-C is an extracellular matrix glycoprotein known to have anti-adhesive characteristics and to be expressed in various human malignant neoplasms. We hypothesized that the expression of tenascin-C would be increased in human malignant pleural mesothelioma, and its accumulation associated with the prognosis of the patients with this disease. METHODS AND RESULTS: Thirty-seven cases of mesothelioma were studied by immunohistochemically using a monoclonal antibody against tenascin-C, and with a semiquantitative scoring system for tenascin-C in different areas of the tumours. In 10 selected cases tenascin-C mRNA in-situ hybridization was also analysed. Since transforming growth factor-beta (TGF-beta) is known to induce both the synthesis of tenascin-C and the growth of mesotheliomas, an immunohistochemical analysis of TGF-beta 1, -beta 2 and -beta 3 was also performed. Normal pleura (n = 7) and metastatic pleural adenocarcinomas (n = 7) were used as controls. Tenascin-C protein was expressed in every histological subtype of malignant mesothelioma, being most prominent in the fibrotic stroma of a tumour, around tumour cells and at the invasive border, whereas tenascin-C mRNA was scarce in tumour cells. The patients with less immunohistochemical expression for tenascin-C tended to live longer (P = 0.028 by Fishers' exact probability test). All mesotheliomas showed positivity for at least one isoform of TGF-beta. CONCLUSIONS: In conclusion, high expression of tenascin-C protein in malignant pleural mesotheliomas may play a role in its invasive growth, and might serve as a prognostic marker of the disease.

Adenocarcinoma↗

PubMed2002

Up-regulation of heme oxygenase-I in alveolar macrophages of newly diagnosed asthmatics.

Exhaled carbon monoxide (CO), which has been found to be elevated in asthma, is generated primarily by heme oxygenase I (HO-I), an enzyme induced by oxidant stress and cytokines. The aim of this study was to assess the distribution and expression of HO-I in various human lung cells in acute and stable asthma. Normal lung tissue biopsies (from 6 non-smoking subjects operated on for a lung tumour) and macrophages from induced sputum (from 5 healthy controls, 5 untreated asthmatics, 7 stable treated asthmatics and 5 asthmatics recovering from exacerbation and being on systemic steroids) were investigated for HO-I by immunohistochemistry. The time response of HO-I induction was examined in cultured monocytes, which are known to maturate into monocyte-derived macrophages in culture. Lung biopsies showed prominent HO-I immunoreactivity only in alveolar macrophages. Macrophages in the induced sputum of healthy controls showed no HO-I immunoreactivity, with the exception of one case. Moderate or intense HO-I immunoreactivity could be observed in alveolar macrophages in 4/5 cases with recent asthma, and 2/7 with stable asthma, but in none ofthe patients treated with systemic corticosteroids for acute exacerbation. Experiments with cultured cells revealed that HO-I was induced by oxidants within the first 24 h, but the induction was reversed during the next 48 h. HO-I is mainly expressed in alveolar macrophages of human lung. Macrophages of induced sputum show prominent but transient HO-I immunoreactivity, in untreated asthmatics, but not in asthmatics treated with corticosteroids.

Adult↗

PubMed2002

Cell specific expression of peroxiredoxins in human lung and pulmonary sarcoidosis.

BACKGROUND: Six proteins of the peroxiredoxin (Prx) family have recently been characterised which have the capacity to decompose hydrogen peroxide in vivo and in vitro. These proteins may have an important role in the protection of human lung against endogenous and exogenous oxidant stress. However, the expression and distribution of these proteins in healthy human lung and diseased lung tissue is unknown. METHODS: The cell specific expression of Prxs in healthy lung tissue from four non-smokers and in parenchymal tissue from 10 subjects with pulmonary sarcoidosis was investigated by immunohistochemistry, and expression of these proteins in various cultured lung cells and cells of bronchoalveolar lavage (BAL) fluid of controls and patients with sarcoidosis was assessed by Western blot analysis. RESULTS: All six Prxs could be synthesised in cultured human lung cells. The bronchial epithelium showed moderate to high expression of Prxs I, III, V and VI, the alveolar epithelium expressed mainly Prxs V and VI, and alveolar macrophages expressed mainly Prxs I and III. Granulomas of subjects with sarcoidosis expressed mainly Prxs I and III. Samples of BAL fluid from controls and from subjects with sarcoidosis had very similar findings, except that Prxs II and III had a tendency for increased immunoreactivity in sarcoidosis tissue. CONCLUSIONS: Prxs I, III, V, and VI, in particular, have prominent and cell specific expression in human lung tissue. High expression of Prxs I and III in granulomas and alveolar macrophages of sarcoidosis parenchyma may have a significant effect on the oxidant burden and the progression of lung injury in this disease.

Biopsy↗

PubMed2002

Prospective population-based study on the survival of patients with lung cancer.

The purpose of this study was to evaluate the change, over 20 yrs, in the survival of lung cancer patients in a population-based study. Information on all patients with lung cancer in a defined geographical area during 1990-1992 (n=602) was prospectively gathered. The survival of these patients was assessed and also compared with the results of a similar study in the same area during the years 1968-1971 (n=446). The 5-yr survival had improved during 20 yrs from 4% to 12%. The 5-yr survival of the patients with squamous cell carcinoma had increased from 6% to 16%, and adenocarcinoma from 4% to 19%, whereas the survival of small cell carcinoma had remained the same (2% and 3%, respectively). Even though the recent patients were older than those of the earlier series the proportion of surgically treated patients had remained the same (16% and 20%), but the 5-yr survival of patients who had been operated on had increased significantly from 23% to 48%. The differences in survival in the second cohort (1990-1992) between histological types (Chi-squared logrank=59.2), tumour, node, metastasis stages (Chi-squared logrank=199.6), symptomatic stages (Chi-squared logrank=120, p<0.001) and treatment (Chi-squared logrank=277) were significant. Based on this study the independent prognostic factors for better survival of lung cancer patients are tumour, node, metastasis stages I and II, surgical treatment and Feinstein's symptomatic stages I and II.

Adenocarcinoma↗

PubMed2001

Expression of gamma-glutamyl cysteine synthetase in nonsmall cell lung carcinoma.

BACKGROUND: The purpose of this study was to investigate expression of gamma glutamyl cysteine synthetase (gamma GCS), the rate-limiting enzyme in glutathione synthesis in nonsmall cell lung carcinoma (NSCLC). METHODS: Eighty-five samples of NSCLC were studied using immunohistochemistry with polyclonal antibodies to the heavy and light subunits of gamma GCS (gamma GCS-h, gamma GCS-l), and the expressions were correlated with apoptosis and patients survival. Further studies were conducted in cultured cells also to investigate the effects of gamma GSC inhibition with buthionine sulfoximine on the cell survival. RESULTS: In the biopsies, gamma GCS-h positivity was found in 71% and gamma GCS-l positivity in 67% of NSCLCs, and they were expressed in all cell lines studied. There was a strong association between the expression of the heavy and light subunits of gamma GCS in NSCLC (P = 0.003). Strong or moderate gamma GCS-h expression was found significantly more often in squamous cell carcinomas (P = 0.00013) and in Grade 1-2 tumors (P = 0.008). There was a significantly higher extent of apoptosis in tumors with a low gamma GCS-h expression (P = 0.016). A similar tendency was observed with gamma GCS-l (P = 0.073). No association was found between patient survival and high or low expression of gamma GCS-l or gamma GCS-h in NSCLCs (P = 0.34 and P = 0.47, respectively). CONCLUSIONS: The results show that gamma GCS is strongly expressed in NSCLCs and probably takes part in the defense of the tumor cells against oxidative damage. This is reflected by the lower extent of apoptosis in tumors with a high gamma GCS expression. Because expression of gamma GCS has been connected with chemoresistance, downregulation of its activity by inhibitors in NSCLC might have putative therapeutic potential in the treatment of lung carcinoma.

Carcinoma, Non-Small-Cell Lung↗

PubMed2001

Up-regulation of thioredoxin and thioredoxin reductase in human malignant pleural mesothelioma.

Thioredoxin (Trx) with a redoxactive dithiol together with NADPH and thioredoxin reductase (TrxR) is a major disulfide reductase regulating cellular redox state and cell proliferation and possibly contributing to the drug resistance of malignant cells. We assessed the Trx system in malignant pleural mesothelioma cell lines, in nonmalignant pleural mesothelium and in biopsies of malignant pleural mesothelioma. The mRNA and immunoreactive proteins of Trx and cytosolic and mitochondrial TrxR were positive in all four human mesothelioma cell lines investigated. Six cases of nonmalignant, histologically healthy pleural mesothelium showed no Trx or TrxR immunoreactivity, whereas immunohistochemistry on 26 biopsies of human malignant pleural mesothelioma showed positive Trx in all cases and positive TrxR in 23 (88%) of the cases. Moderate or strong immunoreactivity for Trx or TrxR was detected in 85% (22 cases) and 61% (14 cases) of the mesothelioma cases, respectively. Both Trx and TrxR staining patterns were mainly diffuse and cytoplasmic, but in 39% of the mesothelioma cases prominent nuclear staining could also be detected. Although staining for Trx and TrxR was seen in tumor cells, no significant association could be demonstrated between Trx or TrxR expression and tumor cell proliferation or apoptosis in the biopsies of mesothelioma. There was no significant association between the intensity of Trx or TrxR immunoreactivity and patient survival, which may possibly be related to moderate or intense Trx and TrxR reactivity in most of the cases. Although the Trx system may have an important role in the drug resistance of malignant mesothelioma, these studies also suggest that multiple factors contribute to the promotion, cell proliferation and apoptosis of malignant mesothelioma cells in vivo.

Adult↗

PubMed2001

Expression and prognostic significance of catalase in malignant mesothelioma.

BACKGROUND: Free radicals and antioxidant enzymes (AOEs) may play a critical role in cell proliferation and in the resistance of malignant cells against cytotoxic drugs and radiation. Malignant mesothelioma is a resistant tumor with high levels of manganese superoxide dismutase, a central superoxide scavenging AOE. In the current study, the authors assessed the expression and prognostic role of catalase, an important hydrogen peroxide scavenging AOE, in malignant pleural mesothelioma. METHODS: Catalase expression was investigated by immunohistochemistry in 5 cases of nonmalignant healthy pleura and in tumor tissue of 32 mesothelioma patients, and by Western blot in 7 continuous human mesothelioma cell lines. The distribution of catalase in mesothelioma cells was assessed by immunoelectron microscopy. Furthermore, to investigate the effect of catalase inhibition in the drug resistance of these cells in vitro, the authors exposed mesothelioma cells with the highest catalase level to epirubicin with and without aminotriazole pretreatment. RESULTS: Nonmalignant mesothelial cells showed no catalase immunoreactivity whereas most mesothelioma cases (24 of 32, 75%) were catalase positive, 17 cases (53%) showing moderate or high expression. Higher catalase expression in mesothelioma was associated with a better prognosis, mean survival rate from diagnosis being 6 and 24 months for negative/low expression and moderate/high expression, respectively. Furthermore, a coordinately high expression of both manganese-superoxide dismutase (Mn-SOD) and catalase predicted even more favorable outcome of the mesothelioma patients. Catalase also could be detected in all mesothelioma cell lines, the most resistant cell line showing the highest protein expression and compartmentalization of catalase mainly to peroxisomes. Aminotriazole inhibition of catalase had a marginal effect on the toxicity caused by epirubicin. CONCLUSIONS: Catalase may have multifactorial effects in malignant cells; high catalase and/or coordinated high expression of Mn-SOD and catalase may decrease tumor progression by modulating the cellular redox state, but enhanced antioxidant capacity of mesothelioma cells also may protect tumor cells against exogenous oxidants, at least in vitro.

Amitrole↗

PubMed2001

Cell-specific expression of manganese superoxide dismutase protein in the lungs of patients with respiratory distress syndrome, chronic lung disease, or persistent pulmonary hypertension.

The developmental profile of manganese superoxide dismutase (MnSOD) and its regulation in hyperoxia vary between species. We hypothesized that MnSOD increases in human lung in response to oxygen treatment, although this response could be restricted to certain cell types and depend on gestational age. Therefore, the cell-specific expression of pulmonary immunoreactive MnSOD protein was investigated during development, and in patients with respiratory distress syndrome (RDS), chronic lung disease (CLD), or persistent pulmonary hypertension (PPHN). Throughout ontogenesis, all cell types expressed MnSOD, but the most intense positivity was found in bronchiolar epithelium and (pre-) type-II pneumocytes. MnSOD protein did not increase during development. The MnSOD staining pattern in arterial endothelium was more intense in RDS patients than in age-matched controls, but this may be related to induction of MnSOD by increased blood flow rather than by oxygen. MnSOD expression in other cell types of RDS, CLD, or PPHN patients did not differ from that in age-matched controls. We conclude that, in terms of mitochondrial enzymatic superoxide scavenging capacity, preterm infants are not more vulnerable than term infants to oxygen-induced lung injury at physiological oxygen concentrations. However, the inability to induce MnSOD in response to oxygen treatment may result in a poor outcome.

Embryonic and Fetal Development↗

PubMed2001

Expression and regulation of hemeoxygenase 1 in healthy human lung and interstitial lung disorders.

Hemeoxygenase 1 (HO-1) has been implicated in the protection of lung tissue against exogenous oxidant exposure. However, the expression and cellular distribution of HO-1 in human lung continue to be poorly characterized. The localization of HO-1 was studied in histopathologically healthy lung from nonsmoking patients with a carcinoid or other lung tumor (5 cases), pulmonary sarcoidosis (13 cases), and chronic interstitial pneumonias (9 cases, usual interstitial pneumonia; 10 cases, desquamative interstitial pneumonia). Immunostaining was graded from 0 (no immunoreactivity) to +++ (intense immunoreactivity). In healthy lung, HO-1 was localized to alveolar macrophages with reactivity varying from moderate to intense, and in bronchial epithelium, alveolar epithelium, endothelium, and interstitium, the immunoreactivity was not detectable or was very low. Sarcoidosis and interstitial pneumonias showed intense HO-1 immunoreactivity in alveolar macrophages in most of the cases and weak to intense immunoreactivity in the granulomas of sarcoidosis. The immunoreactivity of interstitium was negative or weak in the fibrotic areas of the lung and also in the samples of bronchoalveolar lavage fluid obtained from the patients with UIP. Western blotting indicated that HO-1 is up-regulated by exposure of monocytes to formylated peptide, fMLP, which causes respiratory burst in the cells, and that inhibition of HO-1 by tin protoporphyrin potentiates the injury of fMLP-exposed cells. In conclusion, these data show differential distribution of HO-1 in human lung cells and strongly suggest the importance of HO-1, especially in the defense of alveolar macrophages in normal human lung and in the inflammatory, but not in the fibrotic, stage of interstitial lung disorders.

Blotting, Western↗

PubMed2001

Elevated serum levels of type I collagen degradation marker ICTP and tissue inhibitor of metalloproteinase (TIMP) 1 are associated with poor prognosis in lung cancer.

PURPOSE: The aim of this study was to evaluate the correlation between type I collagen degradation marker ICTP, MMP (matrix metalloproteinase)-9, and tissue inhibitor of metalloproteinase (TIMP)-1 and to compare their value as prognostic factors in lung cancer. EXPERIMENTAL DESIGN: From the sera of 141 lung cancer patients, we assessed markers of type I collagen synthesis (PINP and PICP) and degradation (ICTP) by radioimmunoassays, and we assessed MMP-9 and its tissue inhibitor TIMP-1 by ELISA. There were 62 squamous cell carcinomas, 42 adenocarcinomas, 14 small cell carcinomas, and 23 cases with other histology. Seventeen of these patients had advanced disease. Sixty-seven patients had been operated on, 33 had received radiation therapy, 7 had received chemotherapy, and the rest had received other treatment combinations. RESULTS: We examined the relationship between these markers and found a correlation between ICTP and MMP-9 (r = 0.201; P = 0.01) or TIMP-1 (r = 0.415; P = 0.00). Elevated serum concentrations of ICTP (>5 microg/liter) and/or TIMP-1 (>300 ng/ml) correlated with poor prognosis. In univariate regression analysis, ICTP had prognostic value (odds ratio, 1.6462; P < 0.03): the patients with elevated serum concentrations of ICTP (>5 microg/liter) had a 64% higher risk of dying from lung cancer than did patients with opposite values. CONCLUSIONS: Our results indicated that ICTP and TIMP-1 are good prognostic markers in lung cancer. The association between serum MMP-9 and ICTP suggests that MMP-9 could play a role in the degradation of the extracellular matrix producing ICTP in this pathological situation.

Adenocarcinoma↗