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Pauli Puolakkainen

Publications and source records attributed to Pauli Puolakkainen.

At least 19 recordsLinked to original sources
PubMed2006

Matricellular hevin regulates decorin production and collagen assembly.

Matricellular proteins such as SPARC, thrombospondin 1 and 2, and tenascin C and X subserve important functions in extracellular matrix synthesis and cellular adhesion to extracellular matrix. By virtue of its reported interaction with collagen I and deadhesive activity on cells, we hypothesized that hevin, a member of the SPARC gene family, regulates dermal extracellular matrix and collagen fibril formation. We present evidence for an altered collagen matrix and levels of the proteoglycan decorin in the normal dermis and dermal wound bed of hevin-null mice. The dermal elastic modulus was also enhanced in hevin-null animals. The levels of decorin protein secreted by hevin-null dermal fibroblasts were increased by exogenous hevin in vitro, data indicating that hevin might regulate both decorin and collagen fibrillogenesis. We also report a decorin-independent function for hevin in collagen fibrillogenesis. In vitro fibrillogenesis assays indicated that hevin enhanced fibril formation kinetics. Furthermore, cell adhesion assays indicated that cells adhered differently to collagen fibrils formed in the presence of hevin. Our observations support the capacity of hevin to modulate the structure of dermal extracellular matrix, specifically by its regulation of decorin levels and collagen fibril assembly.

Animals↗
PubMed2006

Epidermal growth factor enhances intracellular pH regulation via calcium signaling in acid-exposed primary cultured rabbit gastric epithelial cells.

We have elucidated the role of different ion transporters and epidermal growth factor(EGF) during luminal acid exposure in primary cultured rabbit surface epithelial cells by measuring intracellular calcium and pH. Amiloride, DIDS, or sodium or bicarbonate substitutions were used to inhibit ion transport. During luminal acid exposure the dominant intracellular pH regulator is the Na+/H+ antiport, and bicarbonate transport has only a secondary role, which is uncovered as the Na+/H+ function fails. The decrease in intracellular pH caused by luminal acid was significantly smaller in serosal EGF-treated epithelia than in controls. This defensive function of EGF was abolished by verapamil, BAPTA, and calmidazolium but not by TMB-8. EGF increased intracellular calcium, which was prevented by verapamil but not by TMB-8. EGF enhances gastric epithelial defense against luminal acid by inducing intracellular calcium signaling via plasma membrane verapamil-sensitive calcium channels and thereby enhancing the function of the Na+/H+ antiport.

Animals↗
PubMed2006

Leptin and adiponectin levels in acute pancreatitis.

OBJECTIVES: Obesity is a risk factor for a severe form of acute pancreatitis (AP). Because the underlying mechanisms are poorly known, we studied relationship between the severity of AP and plasma levels of leptin and adiponectin, 2 adipokines regulating the course of systemic inflammation. METHODS: The study comprises 12 patients with severe AP and 12 control patients with mild AP matched by age (+/-10 years), body mass index (+/-3 kg/m), sex, and etiology of AP. Quantikine Human Adiponectin and Quantikine Human Leptin Immunoassays (R&D Systems, Minneapolis, Minn) were used to measure the adipokine levels in the patients' plasma on admission and during the hospital stay. RESULTS: Median leptin concentrations on admission were 6.1 ng/mL (range, 1.6-72.9 ng/mL) in the severe AP group and 9.0 ng/mL (range, 2.5-36.3 ng/mL) in the mild AP group (P > 0.05). In severe AP, the value at days 2 to 4 (7.7 ng/mL; range, 1.6-13.9 ng/mL) did not differ from respective on-admission value (P > 0.05). In mild AP, the value at days 2 to 4 (3.8 ng/mL; range, 1.6-12.9 ng/mL) was lower than the respective on-admission value (P = 0.005). Adiponectin concentrations on admission were 5642 ng/mL (range, 1201-19,400 ng/mL) for severe AP and 6314 ng/mL (range, 1980-24,340 ng/mL) for mild AP (P > 0.05). Maximum variation of adiponectin level (the highest value minus the lowest value) was greater in severe AP than in mild AP (P = 0.001). CONCLUSIONS: In patients matched by age, sex, body mass index, and etiology, the on-admission plasma levels of adiponectin and leptin do not correlate with disease severity, suggesting that the adipokines do not affect the course of AP.

Acute Disease↗
PubMed2006

Upregulated but insufficient generation of activated protein C is associated with development of multiorgan failure in severe acute pancreatitis.

INTRODUCTION: Disturbed protein C (PC) pathway homeostasis might contribute to the development of multiple organ failure (MOF) in acute pancreatitis (AP). We therefore evaluated circulating levels of PC and activated protein C (APC), evaluated monocyte deactivation in AP patients, and determined the relationship of these parameters to MOF. PATIENTS AND METHODS: Thirty-one patients in the intensive care unit were categorized as cases (n = 13, severe AP with MOF) or controls (n = 18, severe AP without MOF). Blood samples were drawn every second day to determine the platelet count, the levels of APC, PC, and D-dimer, and the monocyte HLA-DR expression using flow cytometry. The APC/PC ratio was used to evaluate turnover of PC to APC. RESULTS: During the initial two weeks of hospitalization, low PC levels (<70% of the adult mean) occurred in 92% of cases and 44% of controls (P = 0.008). The minimum APC level was lower in cases than in controls (median 85% versus 97%, P = 0.009). Using 87% as the cut-off value, 8/13 (62%) cases and 3/18 (17%) controls showed reduced APC levels (P = 0.021). A total of 92% of cases and 50% of controls had APC/PC ratios exceeding the upper normal limit (P = 0.013). Plasma samples drawn before MOF showed low PC levels and high APC/PC ratios. HLA-DR-positive monocytes correlated with PC levels (r = 0.38, P < 0.001) and APC levels (r = 0.27, P < 0.001), indicating that the PC pathway was associated with systemic inflammation-triggered immune suppression. CONCLUSION: PC deficiency and decreased APC generation in severe AP probably contributed to a compromised anticoagulant and anti-inflammatory defence. The PC pathway defects were associated with the development of MOF. The data support feasibility of testing the use of APC or PC to improve the clinical outcome in AP.

Acute Disease↗
PubMed2006

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Journal Article↗
PubMed2005

Effect of the ulcerogenic agents ethanol, acetylsalicylic acid and taurocholate on actin cytoskeleton and cell motility in cultured rat gastric mucosal cells.

AIM: To assess the effects of ulcerogenic agents on actin cytoskeleton and cell motility and the contribution of oxidative stress. METHODS: Rat gastric mucosal cell monolayers were cultured on coverslips. The cells were exposed, with or without allopurinol (2 mmol/L), for 15 min to ethanol (10-150 mL/L), ASA (1-20 mmol/L) or taurocholate (1-20 mmol/L), then the cells were processed for actin and vinculin staining. Cell migration after wounding was also measured. RESULTS: Exposure to 10 mL/L ethanol caused divergence of zonula adherens-associated actin bundles of adjacent cells and decreased rate of migration. These actions were opposed by xanthine oxidase inhibitor allopurinol. Exposure to 50 mL/L ethanol induced degradation and divergence of zonula adherens-associated vinculin from adjacent cells, which was, again, partially reverted by allopurinol. With 1 mmol/L ASA actin filaments became shorter and thicker. However, higher concentrations (10, 20 mmol/L) of ASA returned microfilaments thinner and longer, and decreased rate of migration. Zonula adherens-associated actin bundles were moderately distorted with 10 mmol/L ASA and with 10 mmol/L taurocholate. Exposure to taurocholate provoked changes resembling those of ASA. Taurocholate 5-20 mmol/L decreased the rate of migration dose dependently. The effects of ASA and taurocholate were not prevented by allopurinol. CONCLUSION: All ulcerogenic agents decreased the rate of migration dose dependently and induced divergence of zonula adherens-associated actin bundles of adjacent cells. In addition, ethanol and ASA caused degradation of actin cytoskeleton. Oxidative stress seems to underlie ethanol, but not ASA or taurocholate, induced cytoskeletal damage.

Actins↗
PubMed2005

CD2AP contributes to cell migration and adhesion in cultured gastric epithelium.

The potential association of CD2AP with the adherens junction protein E-cadherin, co-localization with the actin cytoskeleton, and involvement in cell migration was investigated in cultured rat gastric mucosal cells. In stationary cells, CD2AP was localized perinuclearly while E-cadherin was expressed along cell-cell contacts and F-actin formed a branched network and adhesion belts. In migrating cells, CD2AP appeared as thread-like accumulations in the leading edges, colocalizing with F-actin and occasionally with E-cadherin. Intracellular injection of anti-CD2AP significantly retarded the migration speed of the cells suggesting a crucial role for CD2AP in mucosal cell migration, possibly as a scaffolding protein between cell membrane proteins and actin cytoskeleton. Co-immunoprecipitation assays revealed that CD2AP and E-cadherin are in a complex in HGF stimulated cells. It is concluded that CD2AP interacts with E-cadherin and co-localizes with F-actin in the leading edge of migrating cells, and significantly contributes to cell migration in restituting gastric epithelium.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Early sequential changes in serum markers of acute pancreatitis induced by endoscopic retrograde cholangiopancreatography.

BACKGROUND/AIMS: Trypsinogen activation is thought to play a crucial role in the pathogenesis of acute pancreatitis (AP). Our aim was to characterize the very early sequential changes of trypsinogen-1, trypsinogen-2, the trypsin-2-alpha1-antitrypsin complex (T2-AAT), and pancreatic secretory trypsin inhibitor (PSTI) in serum from patients with pancreatitis induced by endoscopic retrograde cholangiopancreatography (ERCP), a model for studying the early phase of the disease in humans. PATIENTS AND METHODS: The study population consisted of 659 consecutive patients with 897 ERCP procedures. Blood samples were obtained before and at different time points after the procedure. The serum concentrations of trypsinogen-1 and trypsinogen-2, PSTI and T2-AAT were determined by time-resolved immunofluorometric assays. RESULTS: ERCP-induced pancreatitis developed after 50 of the 897 ERCP procedures (5.6%). Sixty-one randomly selected ERCP patients without post-ERCP pancreatitis served as controls. Trypsinogen-1 and trypsinogen-2 showed an equally steep increase during the two first hours after ERCP in patients developing AP, but trypsinogen-1 decreased more rapidly than trypsinogen-2, which remained elevated during the 5-day study period. Serum PSTI also increased rapidly whereas T2-AAT increased more slowly peaking at 24 h. In patients developing post-ERCP pancreatitis the median concentration of trypsinogen-1 was markedly higher than in the controls already before the ERCP procedure. In the control group the concentrations of trypsinogen-1, trypsinogen-2, PSTI and T2-AAT did not change significantly. CONCLUSIONS: The rapid increase of trypsinogen-1 and trypsinogen-2 and PSTI in the early phase of AP suggests that release of pancreatic enzymes is the initial event while the delayed increase of T2-AAT may reflect that the capacity of the intrapancreatic PSTI-based inhibitory mechanism has been exhausted.

Acute Disease↗
PubMed2005

Helicobacter pylori infection and low serum pepsinogen I level as risk factors for gastric carcinoma.

AIM: To study whether examination of CagA antibodies could increase the odds ratio for gastric cancer in a case-control study, and how often other serum markers of gastric cancer risk could be found in Helicobacter pylori -negative patients. METHODS: H pylori CagA and parietal cell antibodies (PCAs), and serum pepsinogen I (SPGI) levels were compared between patients with gastric cancer and controls who received endoscopic examination due to reasons other than gastrointestinal malignancy. RESULTS: The odds ratio (OR) for gastric cancer was 2.9 (95% CI 1.4-5.8) in H pylori + patients, and 2.4 (95% CI 1.2-4.9) in CagA+ patients. When results of H pylori and CagA antibodies were combined, OR increased to 5.0 (95% CI 2.5-10.0). Furthermore, if cardia cancer patients were excluded, the OR increased to 6.8 (95% CI 3.1-14.8). Among patients with a low SPGI level, the OR was 12.0 (95% CI 4.1-35.3). However, the risk was significant only in the older age group. The number of patients with low SPGI was significantly higher in H pylori -/CagA+ patients as compared to other cancer patients. CONCLUSION: Examination of both H pylori and CagA antibodies increases the OR for gastric cancer in our case-control study. CagA antibodies are important in detecting previous H pylori infection in advanced atrophic gastritis or cancer when spontaneous decline of H pylori antibodies occurs. SPGI may be helpful in screening elderly gastric cancer patients.

Adult↗
PubMed2005

Pancreatic secretory trypsin inhibitor (SPINK1) gene mutations in patients with acute pancreatitis.

OBJECTIVES: Mutations in the secretory trypsin inhibitor (SPINK1) gene have been found to be associated with hereditary and chronic pancreatitis. There are no previous reports on SPINK1 mutations in patients with acute pancreatitis (AP). METHODS: The study population consists of 371 patients with AP, of which 207 patients had mild and 164 had a severe form of the disease. The etiologies of AP were identified. Four hundred fifty-nine blood donors served as controls. SPINK1 N34S and P55S mutations were detected by minisequencing and confirmed by direct sequencing. RESULTS: The N34S mutation was found in 29 (7.8%) of the patients and in 12 (2.6%) of the controls (P < 0.0001, Fisher exact test). There was no difference in the frequency of the P55SS mutation between the groups. A majority of the patients (n = 229; 61.7%) had alcohol-induced AP. The frequency of the N34S mutation was higher in the subgroups of severe AP (15/164; 9.1%) and alcohol-induced AP (21/229; 9.2%), but the differences were not statistically significant. No differences in age at admission and number of attacks of AP were observed between the groups. CONCLUSION: SPINK1 N34S mutation enhances the susceptibility of AP.

Acute Disease↗
PubMed2005

Monocyte anergy is present in patients with severe acute pancreatitis and is significantly alleviated by granulocyte-macrophage colony-stimulating factor and interferon-gamma in vitro.

OBJECTIVES: Severe acute pancreatitis (AP) is frequently associated with immune suppression, which increases the risk of infections, organ failure, and death. Our aims were to measure monocyte function (ie, HLA-DR expression and tumor necrosis factor-alpha [TNF-alpha] production as markers of immune suppression) in patients with severe AP and to determine whether treatment of blood samples with granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or interferon-gamma (IFN-gamma) corrected the functional defects of monocytes in vitro. METHODS: The study consisted of 28 patients with severe AP who were treated at intensive care unit and in whom the proportion of HLA-DR-positive monocytes in the circulation was less than 70%, and 28 matched control subjects who were selected from healthy laboratory personnel. HLA-DR density was determined by whole blood flow cytometry. Monocyte TNF-alpha production in response to bacterial lipopolysaccharides (LPSs) was studied in a whole blood assay. Aliquots of blood were supplemented with IFN-gamma (all 28 patients), GM-CSF (the last 24 patients), or both (the last 12 patients). RESULTS: The median proportion of HLA-DR-positive monocytes was 45% in patients (range, 18%-73%) and was 98% in controls (range, 86%-100%; P < 0.001). TNF-alpha levels in response to LPSs were lower in patients (545 pg/mL; range, 84-1990 pg/mL) than in controls (1415 pg/mL; range, 660-5490 pg/mL; P < 0.001). The proportion of HLA-DR-positive cells correlated positively with TNF-alpha levels (r = 0.56; P < 0.01). Both GM-CSF and IFN-gamma increased HLA-DR expression of monocytes in patients (98%; range, 74%-100% for GM-CSF; 99%; range, 86%-100% for IFN-gamma; both P < 0.001). The combination restored monocyte HLA-DR expression (99%; range, 96%-100%; P = 0.002). Compared with basal levels, GM-CSF increased TNF-alpha production of monocytes both in blood samples from patients (median, 1320 pg/mL; range, 35-8015 pg/mL) and controls (median, 3450 pg/mL; range, 1040-9835 pg/mL; both P < 0.001). IFN-gamma increased TNF-alpha production by monocytes in patients (683 pg/mL; range, 186-2705 pg/mL; P < 0.05) but not in controls (1658 pg/mL; range, 765-4755 pg/mL; P = 0.31). With the combination of GM-CSF and IFN-gamma, the TNF-alpha levels of monocytes in patients (3185 pg/mL; range, 545-8280 pg/mL) and in controls (2800 pg/mL; range, 1080-6860 pg/mL) were comparable. CONCLUSIONS: The proportion of HLA-DR-positive monocytes correlates with TNF-alpha production, and they both reflect the degree of immune suppression. The low proportion of HLA-DR-positive monocytes in AP can be reversed in vitro by GM-CSF and/or IFN-gamma. The GM-CSF and IFN-gamma treatments also increase LPS-induced TNF-alpha production. By the combination of GM-CSF and IFN-gamma, but not by either agent alone, LPS-induced TNF-alpha production of monocytes was equally high in patients and in controls.

Acute Disease↗
PubMed2005

Calcium signaling is involved in ethanol-induced volume decrease and gap junction closure in cultured rat gastric mucosal cells.

Ethanol is a well-established "barrier breaker" in gastric mucosa, but its detailed effects at the cellular level remain unclear. We have previously shown that the intracellular free calcium concentration is increased, gap junctions are closed, and cell volume is decreased after exposure to 5% (v/v) ethanol in primarily cultured rabbit gastric epithelial cells. Rat gastric mucosal (RGM) cells were grown to confluence on a coverslip or on a filter membrane. Gap junctional diffusion was measured in 5-carboxyfluorescein-loaded cells by bleaching a small area with a laser and measuring the recovery with confocal microscope. Intracellular calcium was measured spectrofluorometrically in fura-2-loaded cells. For cell volume measurements the cell monolayer was loaded with calcein and imaged along the Z-axis with a confocal microscope. The changes in fluorescence intensity were intercepted as a measure of cell volume change. TMB-8 was used to inhibit intracellular calcium release and lanthanum to block plasma membrane calcium selective ion channels, while BABTA served as an intracellular calcium chelating agent. Results showed that ethanol (7.5%, v/v) exposure increased intracellular calcium from 69 +/- 7 to 142 +/- 11 nM (N = 5; P < 0.05), decreased cell volume by -23 +/- 5% (N = 8; P < 0.05), and induced gap junction closure (fluorescence recovery from 37 +/- 9 to 15 +/- 3%; N = 6; P < 0.05). A serosal potassium channel blocker, quinine, almost completely prevented the ethanol-induced cell volume decrease (from -23 +/- 5 to -3 +/- 3%), suggesting that opening of basolateral potassium channels underlies cell shrinkage. BABTA inhibited completely (from 35 +/- 3 to 39 +/- 4 nM; N = 6; P < 0.05), and TMB-8 + lanthanum partially (from 60 +/- 6 to 92 +/- 12 nM; N = 6; P < 0.05), the ethanol-induced intracellular calcium increase. BABTA also abolished the ethanol-induced volume decrease (from -23 +/- 5 to 1 +/- 4%; N = 6; P < 0.05), while TMB-8 + lanthanum had a lesser effect on it (from -23 +/- 5 to -11 +/- 3%; N = 9; P < 0.05). They also abolished the closure of gap junctions induced by ethanol (fluorescence recovery, 38 +/- 5% for BABTA and 30 +/- 4% for TMB-8 + lanthanum). We conclude that luminal ethanol opens basolateral calcium-dependent potassium selective channels with resultant shrinkage of the cells and blocks the intercellular gap junctions. These actions are mediated by intracellular calcium signaling.

Animals↗
PubMed2004

Proinflammatory effects of pancreatic elastase are mediated through TLR4 and NF-kappaB.

Pancreatic elastase has been implicated in the pathophysiology of severe acute pancreatitis, characterized by systemic inflammatory response, distant organ failure, and high mortality. Here we show that pancreatic elastase activates transcription factors NF-kappaB, AP-1, and NFAT in human myeloid cells (U-937 and THP-1) in culture. Pancreatic elastase also induces TNF-alpha secretion and increased expression of CD11b in THP-1 cells which can be inhibited by neutralizing anti-Toll-like receptor 4 (TLR4) antibodies. NF-kappaB blocking agents (MG-132, PGA1) prevented elastase-induced TNF-alpha secretion from THP-1 cells. Our results suggest that pancreatic elastase-induced proinflammatory effects are mediated by TLR4 and NF-kappaB in human myeloid cells.

Blotting, Western↗
PubMed2004

Coamplified and overexpressed genes at ERBB2 locus in gastric cancer.

DNA copy number amplification at the chromosomal region of 17q is frequent in gastric cancer. Recently 17q21 was identified as the critical region for the amplicon formation because this region harbors the ERBB2 oncogene and several other targets, such as TOP2A and DARPP32. In our study, we characterized the amplification (52 cases) and expression (29 cases) levels of ERBB2, TOP2A and DARPP32 in gastric cancer samples. These 3 genes were concomitantly amplified in 17% of the intestinal type of gastric adenocarcinoma. However, the expression levels were independent, showing overexpression of DARPP32 (48%), TOP2A (17%) and ERBB2 (3%) studied by quantitative real-time PCR. The most frequently overexpressed gene, DARPP32, exhibited strong protein overexpression in 45% (30/66) of the cases in immunohistochemical study of gastric cancer tumor tissue array. Additional studies are required to thoroughly understand the biological significance of these genes in gastric cancer.

Adenocarcinoma↗
PubMed2003

Cleavage of the matricellular protein SPARC by matrix metalloproteinase 3 produces polypeptides that influence angiogenesis.

SPARC, a matricellular protein that affects cellular adhesion and proliferation, is produced in remodeling tissue and in pathologies involving fibrosis and angiogenesis. In this study we have asked whether peptides generated from cleavage of SPARC in the extracellular milieu can regulate angiogenesis. Matrix metalloproteinase (MMP)-3, but not MMP-1 or 9, showed significant activity toward SPARC. Limited digestion of recombinant human (rhu)SPARC with purified catalytic domain of rhuMMP-3 produced three major fragments, which were sequenced after purification by HPLC. Three synthetic peptides (Z-1, Z-2, and Z-3) representing motifs from each fragment were tested in distinct assays of angiogenesis. Peptide Z-1 (3.9 kDa, containing a Cu2+-binding sequence KHGK) exhibited a biphasic effect on [3H]thymidine incorporation by cultured endothelial cells and stimulated vascular growth in the chick chorioallantoic membrane (CAM). In contrast, peptides Z-2 (6.1 kDa, containing Ca2+-binding EF hand-1) and Z-3 (2.2 kDa, containing neither Cu2+-binding motifs nor EF hands), inhibited cell proliferation in a concentration-dependent manner and exhibited no effects on vessel growth in the CAM. Reciprocal results were obtained in a migration assay in native collagen gels: peptide Z-1 was ineffective over a range of concentrations, whereas Z-2 or Z-3 stimulated cell migration. Therefore, proteolysis of SPARC by MMP-3 produced peptides that regulate endothelial cell proliferation and/or migration in vitro in a mutually exclusive manner. One of these peptides containing KHGK also demonstrated a concentration-dependent effect on angiogenesis.

Amino Acid Sequence↗
PubMed2003

Trypsinogen-2 and trypsinogen activation peptide (TAP) in urine of patients with acute pancreatitis.

BACKGROUND AND AIMS: There is an obvious clinical need for a simple test that can identify patients at risk of developing severe acute pancreatitis. In this work we compared urinary trypsinogen-2 with urinary trypsinogen activation peptide (TAP) and serum C-reactive protein (CRP) for early differentiation between mild and severe acute pancreatitis. PATIENTS AND METHODS: The study population consisted of 127 consecutive patients with acute pancreatitis of whom 29 had severe disease. Urinary trypsinogen-2 was measured by a quantitative immunofluorometric assay and TAP by a competitive immunoassay. Serum CRP was determined by immunoturbidimetry. RESULTS: The sensitivity and specificity to identify severe acute pancreatitis on admission was 72% and 81% for urinary trypsinogen-2, 64% and 82% for urinary TAP, and 29% and 93% for serum CRP, respectively. At 24 h after admission, the values were 82% and 78% for urinary trypsinogen-2, 52% and 92% for urinary TAP, and 84% and 72% for serum CRP, respectively. Receiver-operating characteristics curve analysis showed that the area under the curve was larger for urinary trypsinogen-2 than for urinary TAP and serum CRP on admission and 24 h after admission. On admission the positive likelihood ration for urinary trypsiongen-2 was 3.7, for urinary TAP 3.6, and 4.3 for serum CRP, respectively. The corresponding negative likelihood ratios were 0.34, 0.43, and 0.76, respectively. CONCLUSION: Urinary trypsinogen-2 was superior to serum CRP and as god as or even better than urinary TAP and in the early prediction of disease severity in acute pancreatitis. These results suggest that it could be a valuable adjunct in the early assessment of the severity of acute pancreatitis.

APACHE↗