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Biomedical subjects

Matthias Müller

Publications and source records attributed to Matthias Müller.

At least 37 records · Page 2Linked to original sources
PubMed2004

Differential effects of everolimus and cyclosporine A on intimal alpha-actin-positive cell dynamics of carotid allografts in mice.

BACKGROUND: We recently demonstrated that donor medial cells are replaced by smooth muscle alpha-actin (SMA)-expressing host cells in murine carotid allografts. In this study, we investigated neointimal cell dynamics including effects of cyclosporine A (CsA) and everolimus (SDZ RAD, Certican). To obtain a functional readout, we measured the effects of these treatments on cardiac allografts. METHODS: Heterotopic heart allotransplantation was performed between C57BL/6 (B6) and BALB/c (B/c) mice. Orthotopic carotid artery allotransplantation was performed between B6 and B/c mice expressing green fluorescent protein (GFP). Both strains served as donors and recipients. Groups of mice were treated for 4 and 8 weeks (heart and carotid recipients, respectively) with placebo, CsA 20 mg/kg per day, or everolimus 1.0 mg/kg per day using Alzet minipumps. At 2, 4, and 8 weeks, carotid grafts were harvested for histology. RESULTS: In the GFP-B/c to B6 strain combination, everolimus but not CsA significantly reduced neointima formation and accumulation of SMA-positive host (non-GFP) cells at doses that did not fully suppress heart rejection. In the B6 to GFP-B/c strain combination, everolimus and CsA strongly prevented heart rejection under treatment, partly suppressed neointima formation, and completely prevented SMA-positive host (GFP) cell accumulation. CONCLUSIONS: Donor-derived cells expressing SMA never appear in the neointima, and such cells are completely recipient derived. Adequate immunosuppression delays or prevents the disappearance of donor cells and the appearance of host cells in the graft, a phenomenon apparently associated with the neointima formation. Even immunosuppression sufficient to prevent heart allograft rejection under treatment completely, diminishes neointima formation only by approximately 50%.

Actins↗
PubMed2004

Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice.

GABAB receptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABAB receptors are usually only observed after coexpression of GABAB(1) and GABAB(2) subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABAB(1) is responsible for binding of GABA, whereas GABAB(2) is necessary for surface trafficking and G-protein coupling. Consistent with these in vitro observations, the GABAB(1) subunit is also essential for all GABAB signaling in vivo. Mice lacking the GABAB(1) subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABAB agonists. However, GABAB(1) exhibits a broader cellular expression pattern than GABAB(2), suggesting that GABAB(1) could be functional in the absence of GABAB(2). We now generated GABAB(2)-deficient mice to analyze whether GABAB(1) has the potential to signal without GABAB(2) in neurons. We show that GABAB(2)-/- mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABAB(1)-/- mice. This clearly demonstrates that the lack of heteromeric GABAB(1,2) receptors underlies these phenotypes. To our surprise and in contrast to GABAB(1)-/- mice, we still detect atypical electrophysiological GABAB responses in hippocampal slices of GABAB(2)-/- mice. Furthermore, in the absence of GABAB(2), the GABAB(1) protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABAB(2) with GABAB(1) is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABAB receptors exist in neurons that naturally lack GABAB(2) subunits.

Animals↗
PubMed2004

Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting.

OBJECTIVE: This evaluation focuses on polymorphisms of the cytochrome-P450 (CYP) isoenzymes 2C9, 2C19 and 2D6 and their association with plasma concentrations within a typical clinical setting. Side effects and treatment response were analysed in an exploratory approach in poor and ultra-rapid metabolisers. PATIENTS AND METHODS: We analysed 136 Caucasian depressed inpatients treated with amitriptyline, citalopram, clomipramine, doxepin, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine, who underwent weekly plasma concentration measurements, assessment of the severity of illness and side effects during their stay in the hospital. Patients were genotyped with respect to CYP2C9 alleles *1 and *2, the CYP2C19 alleles *1, *2 and *3 and the CYP2D6 alleles *1 to *9 and CYP2D6 gene duplication. RESULTS: CYP2D6 poor metaboliser genotype and co-medication with inhibitors of CYP2D6 were associated with higher plasma concentrations than the drug-specific median plasma concentration when normalised to dose; plasma concentrations of CYP2C19 extensive metabolisers and smokers were significantly lower than the drug-specific median. Five of the six CYP2D6 poor metabolisers experienced side effects. Response was not associated with plasma concentrations above or below the lower limit of a presumed therapeutic range. CONCLUSION: These data indicate a significant influence of the CYP2D6 genotype, minor influence of the CYP2C19 genotype and no influence of the CYP2C9 genotype on plasma concentrations of patients taking mainly second-generation antidepressants. Because of the good tolerability of the latter and the flat dose-response relationship, genotyping should only be considered in cases of suspected side effects.

Antidepressive Agents↗
PubMed2004

Floxed allele for conditional inactivation of the GABAB(1) gene.

GABA(B) receptors are the G-protein-coupled receptors for the neurotransmitter GABA. GABA(B) receptors are broadly expressed in the nervous system. Their complete absence in mice causes premature lethality or--when mice are viable--epilepsy, impaired memory, hyperalgesia, hypothermia, and hyperactivity. A spatially and temporally restricted loss of GABA(B) function would allow addressing how the absence of GABA(B) receptors leads to these diverse phenotypes. To permit a conditional gene inactivation, we flanked critical exons of the GABA(B(1)) gene with lox511 sites. GABA(B(1)) (lox511/lox511) mice exhibit normal levels of GABA(B(1)) protein, are fertile, and do not display any behavioral phenotype. We crossed GABA(B(1)) (lox511/lox511) with Cre-deleter mice to produce mice with an unrestricted GABA(B) receptor elimination. These GABA(B(1)) (-/-) mice no longer synthesize GABA(B(1)) protein and exhibit the expected behavioral abnormalities. The conditional GABA(B(1)) allele described here is therefore suitable for generating mice with a site- and time-specific loss of GABA(B) function.

Alleles↗
PubMed2004

The effect of intravenous quinaprilat on plasma cytokines and hemodynamic variables during cardiac surgery.

OBJECTIVES: Perioperative treatment with angiotensin-converting enzyme (ACE) inhibitors in cardiac surgery with cardiopulmonary bypass is still controversial. Using ACE inhibitors during cardiac surgery might be associated with an increased risk of critical hypotensive episodes. On the other hand, ACE inhibitors could have beneficial effects with respect to the development of the systemic inflammatory response syndrome. DESIGN: The effect of acute administration of quinaprilat on hemodynamic variables and plasma cytokines was assessed under double-blind, randomized, and placebo-controlled conditions. SETTING: Department of anesthesiology and cardiovascular surgery clinic in a university hospital. PARTICIPANTS: Forty patients without preexisting cardiac failure, undergoing coronary artery bypass grafting. INTERVENTIONS: Patients received 0.08 mg/kg of intravenous quinaprilat or intravenous isotonic saline solution after induction of anesthesia. MEASUREMENTS AND RESULTS: Blood samples were taken after induction of anesthesia (T0), before cardiopulmonary bypass (T1), at the end of surgery (T2), and 4 hours after the end of surgery (T3). There was no difference between the 2 groups regarding mean arterial pressure and inotropic or vasopressor support. Systemic vascular resistance index was significantly lower in the quinaprilat group at T2 (p = 0.016) and T3 (p = 0.017). No difference in proinflammatory cytokine levels was observed between the 2 groups. CONCLUSIONS: The present investigation shows that acute administration of an intravenous ACE inhibitor, quinaprilat, has no influence on proinflammatory cytokines during cardiac surgery with cardiopulmonary bypass. The patients treated with quinaprilat showed an improved systemic vascular resistance index with no increased risk of deleterious hemodynamic episodes.

Angiotensin II↗
PubMed2004

Transesophageal echocardiography as a guide for patient positioning before neurosurgical procedures in semi-sitting position.

With an incidence of a patent foramen ovale in nearly one fourth of the normal population, neurosurgical procedures in the semi-sitting position are associated with the risk of paradoxical air embolism. The present study was undertaken to evaluate an anesthetic concept to detect a patent foramen ovale with the help of transesophageal echocardiography in anesthetized patients before neurosurgical procedures in the semi-sitting position. Transesophageal echocardiography was performed after induction of anesthesia before surgery to avoid additional physical and psychologic stress for the patients. Thirty-five neurosurgical patients scheduled for elective surgery in the semi-sitting position were examined with help of contrast transesophageal echocardiography. The data of the examined patients were analyzed with respect to efficiency, logistic efforts, and adverse events. Contrast transesophageal echocardiography was combined with a ventilation maneuver to increase right atrial pressure. A patent foramen ovale was detected in 3 of 35 patients. These patients were operated on in a supine position. Oral insertion of the echoprobe was possible in all patients without difficulties. A short-lasting hypertension was observed in 5 patients despite adequate analgesia and sedation. The average time of examination was 25 minutes. None of the patients showed paradoxical air embolism as judged by postoperative neurologic assessment. Contrast transesophageal echocardiography combined with a ventilation maneuver is an effective method in detecting a patent foramen ovale. Moreover, transesophageal echocardiography is a clinical guide to patient positioning. The method of anesthetic management presented to examine anesthetized patients immediately before surgery means less physical and psychologic stress for the patients and causes approximately a 30-minute delay of surgery.

Adult↗
PubMed2004

Perioperative management in pediatric heart transplantation from 1988 to 2001: anesthetic experience in a single center.

Pediatric cardiac transplantation is currently an accepted option for end-stage heart disease and congenital cardiac malformations. This report focuses on the anesthetic perioperative management in 12 yr. From 1988 to 2001 we performed 90 heart transplantations in 88 children, infants and neonates. The pediatric heart transplant program of the children's heart center at our university hospital started in June 1988 with the transplantation of a 2-yr-old boy who was suffering from congenital heart disease. Since then, 88 transplants have been performed. We divided our patients into two groups. Group 1 ranged from 1988 to 1996 and Group 2 from 1997 to 2001. The patient characteristics have not significantly changed over the years in our institution. At the time of transplantation, mean age of the patients was 2.6 +/- 4.3 yr from the period of 1988-1996 and 2.5 +/- 4.1 yr from 1997 to 2001. Since 1988, 90 transplants (Tx) in 88 patients have been performed. Two patients needed re-Tx within 2 days after the initial operation because of primary graft failure. Indications for Tx were congenital heart disease (n = 67) and cardiomyopathy (n = 21). In the subgroup of the patients suffering from congenital heart disease there were 46 with the diagnosis of HLHS, followed by endocardial fibroelastosis (n = 7); the remaining 14 patients had other complex cardiac malformations and some underwent corrective palliative cardiac surgery before Tx. Sixty-three patients were younger than 1 yr of age and only five children were older than 10 yr. Twenty-three percent of the patients on the waiting list died before Tx was possible. The overall survival rate was 79% at 1 yr and 73% at 5 and 10 yr. Infants with HLHS had a lower probability of survival after 5 yr compared with other diagnosis (69% vs. 84%). Until now 21 patients have died after Tx. The duration of anesthesia, time of CPB and the age at the time of surgery decreased over the years. It is always a challenge for the anesthesiologist to treat these patients with pulmonary hypertension as one of the most critical risks in this group of patients. The preventive therapy with vasodilators as well as the availability of mechanical assist devices before and after heart transplantation reduces the effects of transitional pulmonary hypertension and prevents the development of post-operative right heart failure.

Anesthesia↗
PubMed2004

Membrane targeting of a bacterial virulence factor harbouring an extended signal peptide.

Filamentous haemagglutinin (FHA) is the major adhesin of Bordetella pertussis, the whooping cough agent. FHA is synthesized as a 367-kDa precursor harbouring a remarkably long signal peptide with an N-terminal extension that is conserved among related virulence proteins. FHA is secreted via the two-partner secretion pathway that involves transport across the outer membrane by a cognate transporter protein. Here we have analyzed the mechanism by which FHA is targeted to, and translocated across, the inner membrane. Studies were performed both in vitro using Escherichia coli inside-out inner membrane vesicles and in vivo by pulse-chase labelling of Bordetella pertussis cells. The data collectively indicate that like classical periplasmic and outer membrane proteins, FHA requires SecA and SecB for its export through the SecYEG translocon in the inner membrane. Although short nascent chains of FHA were found to cross-link to signal recognition particle (SRP), we did not obtain indication for an SRP-dependent, co-translational membrane targeting provoked by the FHA signal sequence. Our results rule out that the extended signal peptide of FHA determines a specific mode of membrane targeting but rather suggest that it might influence the export rate at the inner membrane.

Adenosine Triphosphatases↗
PubMed2004

Interactive blood simulation for virtual surgery based on smoothed particle hydrodynamics.

In this paper, we propose an interactive method based on Smoothed Particle Hydrodynamics (SPH) to simulate blood as a fluid with free surfaces. While SPH was originally designed to simulate astronomical objects, we gear the method towards fluid simulation by deriving the force density fields directly from the Navier-Stokes equation and by adding a term to model surface tension effects. In contrast to Eulerian grid-based approaches, the particle-based approach makes mass conservation equations and convection terms dispensable which reduces the complexity of the simulation. In addition, the particles can directly be used to render the surface of the fluid. Our method can be used in interactive surgical training systems with models of up to 3000 particles.

Aneurysm↗
PubMed2003

Dynamics of medial smooth muscle changes after carotid artery transplantation in transgenic mice expressing green fluorescent protein.

BACKGROUND: Recent observations have demonstrated the importance of host cells in neointima formation after transplantation. Because little is known regarding the dynamics of host-derived cells in the graft media, we investigated this question in a mouse carotid artery transplantation model. METHODS: C57BL/6 carotid arteries were orthotopically transplanted into BALB/c mice ubiquitously expressing enhanced green fluorescent protein. Grafts were harvested at 1, 2, 4, and 8 weeks after transplantation for histologic examination. No immunosuppression was used. RESULTS: Immunostaining and semiquantitative analysis of cross sections showed that donor medial smooth muscle cells decreased over time in the graft media, whereas green fluorescent protein-positive/smooth muscle alpha-actin-positive cells (i.e., cells of host origin) increased over time. Interestingly, host cells were located only in the inner media and the neointima at 2 weeks and thereafter also in the outer media, indicating that the host-derived cells entered the media from the luminal side rather than from the adventitia. In longitudinal sections, there were no differences in the accumulation of donor- and host-derived cells between the end and middle regions of the graft media at 8 weeks. CONCLUSIONS: After transplantation, medial cells were replaced by alpha-actin-expressing host cells that were probably derived from circulating precursor cells. Our observations differ from the traditional view of a major contribution of donor medial smooth muscle cells to the neointima formation. Thus, circulating progenitor cells may be important for graft vessel disease.

Animals↗
PubMed2003

Transgenic rat hearts overexpressing SERCA2a show improved contractility under baseline conditions and pressure overload.

OBJECTIVE: The activity of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) is reduced in the failing myocardium. Therefore, transfer of SERCA2a cDNA is considered as a therapeutical approach. The aim of this study was analysis of the long-term effect of SERCA2a overexpression in normal as well as pressure overload challenged myocardium of transgenic rats. METHODS: Independent transgenic rat lines were established expressing the rat SERCA2a cDNA specifically in the myocardium resulting in increased SERCA2a protein levels by 30-70%. Simultaneous measurements of isometric contraction and calcium transients were carried out in right ventricular papillary muscle preparations. Hemodynamic parameters were measured in hearts of unchallenged rats as well as 10 weeks after pressure overload induced by abdominal aortic banding. RESULTS: Analysis of calcium handling and contractile parameters in isolated right ventricular papillary muscles revealed significant shortening of intracellular calcium transients and half maximal relaxation times (RT(50)). Assessing myocardial contractility in working heart preparations, both transgenic rat lines revealed elevated left ventricular pressure, improved systolic and diastolic parameters, attenuated negative force-frequency relation, and a dose-dependent beta-adrenergic effect. Aortic banding resulted in reduction of left ventricular pressure and worsening of contraction and relaxation parameters with no differences in mortality in both transgenic (+dP/dt 3084+/-96 vs. 3938+/-250 mmHg/s; RT(50) 47.0+/-1.2 vs. 36.7+/-1.4 ms) and wild-type rats (+dP/dt 2695+/-86 vs. 3297+/-122 mmHg/s; RT(50) 53.0+/-1.6 vs. 44.1+/-1.4). SERCA2a overexpressing hearts revealed improved hemodynamic parameters compared to wild-type controls. Acceleration of isovolumetric relaxation characterized by the index Tau was directly correlated to SERCA2a protein concentrations. CONCLUSION: Overexpression of SERCA2a protein results in a positive inotropic effect under baseline conditions remaining preserved under pressure overload without affecting mortality. Therefore therapeutic transfer of SERCA2a may become a potential approach for gene therapy of congestive heart failure. Moreover, transgenic SERCA2a rats will be useful for studies of long-term SERCA2a overexpression in further cardiovascular disease models.

Animals↗
PubMed2003

Export of beta-lactamase is independent of the signal recognition particle.

In Escherichia coli, three different types of proteins engage the SecY translocon of the inner bacterial membrane for translocation or insertion: 1) polytopic membrane proteins that prior to their insertion into the membrane are targeted to the translocon using the bacterial signal recognition particle (SRP) and its receptor; 2) secretory proteins that are targeted to and translocated across the SecY translocon in a SecA- and SecB-dependent reaction; and 3) membrane proteins with large periplasmic domains, requiring SRP for targeting and SecA for the translocation of the periplasmic moiety. In addition to its role as a targeting device for membrane proteins, a function of the bacterial SRP in the export of SecB-independent secretory proteins has also been postulated. In particular, beta-lactamase, a hydrolytic enzyme responsible for cleavage of the beta-lactam ring containing antibiotics, is considered to be recognized and targeted by SRP. To examine the role of the SRP pathway in beta-lactamase targeting and export, we performed a detailed in vitro analysis. Chemical cross-linking and membrane binding assays did not reveal any significant interaction between SRP and beta-lactamase nascent chains. More importantly, membrane vesicles prepared from mutants lacking a functional SRP pathway did block the integration of SRP-dependent membrane proteins but supported the export of beta-lactamase in the same way as that of the SRP-independent protein OmpA. These data demonstrate that in contrast to previous results, the bacterial SRP is not involved in the export of beta-lactamase and further suggest that secretory proteins of Gram-negative bacteria in general are not substrates of SRP.

Biological Transport↗
PubMed2003

First clinical results of the Locking Compression Plate (LCP).

The Locking Compression Plate (LCP) is a new screw-plate system that offers the possibility of inserting conventional and locking head screws into the specially designed combination holes. It represents a further development of the PC-Fix and the LISS and was released for clinical application in March 2000. In a prospective multicentre study, the new system was used to treat 144 patients (f: 67, m: 77; average age: 51.4 years) with 169 fractures: of these, 57 were tibial fractures, 45 humerus, 19 radius and 18 femoral. After one year, clinical and radiological follow-up assessment was carried out on 127 patients with 151 fractures (88%). In 130 fractures (86%), healing took place within the expected period and without complication or secondary dislocation ("uneventful healing"). In 19 patients, a total of 27 unexpected complications occurred ("adverse events"), in which 18 revision operations were necessary in 13 patients: five for implant loosening/pull-out, four for plate failure, one for non-union, five for secondary fractures immediately adjacent to the implant after a subsequent injury and two for infection. Analysis by a committee of experts indicated that mechanical complications arose entirely from technical errors of application (incorrect fixation technique, incorrect choice of plate). No purely implant-related complications were observed. The new system can be regarded as technically mature. It offers numerous fixation possibilities and has proven its worth in complex fractures situations and in revision operations after the failure of other implants. A good knowledge of biomechanics is essential as well as precise preoperative planning.

Adolescent↗
PubMed2003

Ventricular cardiac-assist devices in infants and children: anesthetic considerations.

OBJECTIVE: The application of a mechanical cardiac-assist device is now a common procedure in modern cardiac surgery in patients with end-stage failure, whereas in pediatric patients it is still a great challenge. In the recent literature, a broad range of survival and weaning rates have been reported, depending on the variety of mechanical devices and the choice of patients with different conditions before implantation or if the device is used in emergency surgery. In this article, the authors report their experience with pediatric cardiac-assist devices and the perioperative anesthesia management in this group of patients. PATIENTS AND METHODS: From 1997 to 2001, 11 infants and children were supported with a left and/or right ventricular-assist device. Diagnosis included myocarditis and complex cardiac malformations (hypoplastic left heart syndrome, tetralogy of Fallot with cardiomyopathy, and combined heart defects). The data sets of all patients were recorded using the online anesthesia record-keeping system NarkoData (IMESO GmbH, Hüttenberg, Germany). The program collects all perioperative data during surgery and during a stay in the PACU, including vital signs, administered drugs, as well as the data set of the German Society of Anesthesiology and Intensive Care Medicine. RESULTS: All patients were divided into 2 groups: group 1 = survivors and group 2 = nonsurvivors. A total of 5 patients were in group 1, and group 2 consisted of 6 patients. The duration of anesthesia in group 1 patients (173.2 +/- 95.1 minutes) was significantly (p < 0.05) shorter than in group 2 (631.1 +/- 258.8 minutes) as well as the amount of packed red cells (group 1= 540.5 +/- 150.3 mL, group 2 = 880.6 +/- 400.3 mL). Cardiopulmonary bypass before implantation of a VAD was necessary only in 2 patients from group 1, whereas 5 patients in group 2 were on pump during the procedure. The rate of aortic cross-clamping was also significantly lower in group 1 than in group 2 (p < 0.05). CONCLUSIONS: The surgical outcome depends on the patient's condition at the time of surgery. Emergency surgery, preoperative multiorgan failure, and the need for an extracorporeal circulation with aortic cross-clamping seem to predict a negative outcome in this group of patients.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Differential interactions between a twin-arginine signal peptide and its translocase in Escherichia coli.

The twin-arginine translocation (Tat) machinery of the Escherichia coli inner membrane is dedicated to the export of proteins harboring a conserved SRRxFLK motif in their signal sequence. TatA, TatB, and TatC are the functionally essential constituents of the Tat machinery, but their precise function is unknown. Using site-specific crosslinking, we have analyzed interactions of the twin-arginine precursor preSufI with the Tat proteins upon targeting to inner membrane vesicles. TatA association is observed only in the presence of a transmembrane H(+) gradient. TatB is found in contact with the entire signal sequence and adjacent parts of mature SufI. Interaction of TatC with preSufI is, however, restricted to a discrete area around the consensus motif. The results reveal a hierarchy in targeting of a Tat substrate such that for the primary interaction, TatC is both necessary and sufficient while a subsequent association with TatB likely mediates transfer from TatC to the actual Tat pore.

Cell Membrane↗
PubMed2003

A combined stage 1 and 2 repair for hypoplastic left heart syndrome: anaesthetic considerations.

Therapy of hypoplastic left heart syndrome (HLHS) consists of the staged Norwood procedure or cardiac transplantation. Stenting the ductus arteriosus and subsequent banding of the pulmonary arteries allows the combination of neoaortic reconstruction with the establishment of a bidirectional cavopulmonary connection (combined stage 1 and 2 procedure) in a later session. We report the anaesthetic management in eight infants ranging from 107 to 195 days undergoing a combined stage 1 and 2 procedure. Nonselective pulmonary vasodilators and nitric oxide were needed in all cases to improve oxygen saturation in the postbypass period. Phosphodiesterase inhibitors and epinephrine were required in all patients for inotropic support during and after weaning off cardiopulmonary bypass. The procedure was successful in seven patients. One patient died intraoperatively because of right heart failure. The physiological changes of this new surgical strategy for palliation of HLHS offers a challenge for the anaesthetist primarily in the early postbypass period.

Anesthetics, Intravenous↗
PubMed2003

Matrix metalloproteinase-19 expression in normal and diseased skin: dysregulation by epidermal proliferation.

Most of the matrix metalloproteinases (MMP) are not expressed in normal intact skin but they are upregulated in inflamed or diseased skin. The recently cloned MMP-19 is one of the few MMP members that are also expressed in healthy epidermis. In this study, we found that MMP-19 is generally coexpressed with cytokeratin 14 that is confined to keratinocytes of the stratum basale. MMP-19 was also detected in hair follicles, sebaceous glands, and eccrine sweat glands. Its expression, however, changed in cutaneous diseases exhibiting increased alternations of epidermal proliferation, such as psoriasis, eczema, and tinea. In the affected area, MMP-19 was also found in suprabasal and spinous epidermal layers. We also studied the regulation of MMP-19 expression at the protein level, as well as by using a promoter assay. The constitutive expression of MMP-19 was upregulated with phorbol myristate acetate and downregulated with retinoic acid and dexamethasone. Tumor necrosis factor-alpha, interleukin (IL)-6, TGF-beta, IL-15, IL-8, and RANTES as well as the bacterial compounds lipopolysaccharide and lipoteichoic acid did not show any profound effect in HaCaT cells. In contrast, type IV and type I collagens upregulated MMP-19 significantly. The dysregulation of MMP-19 expression in epidermis suggests its possible involvement in the perpetuation of cutaneous infections and proliferative disorders such as psoriasis.

Blood Vessels↗