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Hi, folks. Not to bore anyone, but for anyone who might be interested, I'm posting this new information (quite lengthy, my apologies, so be pre-warned), but again, I've highlighted and provided comments for easier reading. Hopefully, this will be enough to prove my case for pushing for clinical trial for desipramine. Timothy Coetzee at the NMSS was correct in that he said I should narrow down the focus of what desipramine should be put into clinical trial for. What outcome do we want measured? Ok....I'm getting there. I say this application should be focused first on progressive MS, prevention and regeneration in MS. This is as narrow as I can get. And even that kind of makes me nervous, because that is still leaving out so many other beneficial effects of desipramine (such as its affects on immune system regulation, etc.), but ok. So be it. I'm just a big picture person, I guess.

My original research was just a compilation of bottom line statements on what I found desipramine affects. If you will note, I originally stated that I considered desipramine to be more "preventative and regenerative" and levetiracetam to be more "neuro-protective". Well, my last big posting here included some substantiation for my suspicions about desipramine being "preventative", and today I'm posting substantiation for my suspicions that desipramine may also be "regenerative".

Consider this all something of a correction for my lack of footnotes on my first pass at all this. (And this still doesn't cover everything I found over a period of weeks.) Again, this is not in formal presentation, but after this, I hope I've made my case, and can find someone who will either prove me dead wrong, or get to work on taking this to clinical trial!

I still say (to the MS scientific community), pull desipramine out of the lab and off the shelf and test it directly on progressive MSers, who believe me, would be MORE than happy to try ANYTHING!

Here we go:

My prior substantive material related more to desipramine’s probable effect on prevention of axonal injury in MS. This is substantive material relating to desipramine’s probable effects on axonal regeneration, as previously mentioned in my original research narrative.

The odd thing that is in the back of my mind now, is how uncanny it would be if desipramine could be proven to help remyelination and axonal regeneration at the same time, as I hypothesized in my original narrative. I think I did read somewhere that interfering with myelin inhibitors of axon growth, doesn’t affect the actual process of remyelination itself, since it’s a separate process. (I’ll let that one hang in the back of our minds for now.)


Nat Neurosci. 2004 Mar;7(3):261-8. Epub 2004 Feb 08. Related Articles, Links


PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration.

Sivasankaran R, Pei J, Wang KC, Zhang YP, Shields CB, Xu XM, He Z.

Division of Neuroscience, 320 Longwood Avenue, Children's Hospital, Boston, Massachusetts 02115, USA.

Successful axon regeneration in the mammalian central nervous system (CNS) is at least partially compromised due to the inhibitors associated with myelin and glial scar. However, the intracellular signaling mechanisms underlying these inhibitory activities are largely unknown. Here we provide biochemical and functional evidence that conventional isoforms of protein kinase C (PKC) are key components in the signaling pathways that mediate the inhibitory activities of myelin components and chondroitin sulfate proteoglycans (CSPGs), the major class of inhibitors in the glial scar. Both the myelin inhibitors and CSPGs induce PKC activation. Blocking PKC activity pharmacologically and genetically attenuates the ability of CNS myelin and CSPGs to activate Rho and inhibit neurite outgrowth. Intrathecal infusion of a PKC inhibitor, Go6976, into the site of dorsal hemisection promotes regeneration of dorsal column axons across and beyond the lesion site in adult rats. Thus, perturbing PKC activity could represent a therapeutic approach to stimulating axon regeneration after brain and spinal cord injuries.

PMID: 14770187 [PubMed - indexed for MEDLINE]
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COMMENT FROM DEB: Ok, next I wanted to see if desipramine might work some magic on PKC inhibition.

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Effect of the tricyclic antidepressant desipramine on protein kinase C in rat brain and rabbit platelets in vitro.

Morishita S, Watanabe S.

Department for Psychiatry, Kawasaki Medical School, Kurashiki, Japan.

Protein kinase C (PKC), which participates in cellular responses to various stimuli such as hormones, neurotransmitters and growth factors, is essential for cell proliferation and differentiation. Desipramine, which is a tricyclic antidepressant, inhibited PKC activity in concentrations starting from 0.1 mmol/L in rat brain and its inhibitory effect on PKC activity did not involve competitive inhibition with calcium. However, rabbit platelets incubated with desipramine showed a biphasic dose-response change in PKC activity in vitro. The stimulatory effect of desipramine on PKC activity in rabbit platelets was observed over a concentration range of 0.5-2.0 mmol/L, and an inhibitory effect on PKC activity in platelets began to be seen at a concentration of 3.0 mmol/L desipramine. The stimulatory effects of desipramine and calcium on PKC activity in platelets appear to be occurring by the same mechanism. Several lines of evidence indicate that neurotransmitter uptake is linked to PKC activation. The present study supposes that the inhibitory effect of desipramine on neurotransmitter uptake may, at least in part, be associated with its inhibitory or stimulatory effect on PKC.

PMID: 9316173 [PubMed - indexed for MEDLINE]
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Psychiatry Clin Neurosci. 1999 Feb;53(1):11-5.
Related Articles, Links

Different effect of desipramine on protein kinase C in platelets between bipolar and major depressive disorders.

Morishita S, Aoki S, Watanabe S.

Department of Psychiatry, Kawasaki Medical School, Kurashiki, Okayama, Japan.

Protein kinase C (PKC) activity was investigated in platelets from affective disorder subjects and healthy volunteers. The PKC activity of platelets incubated with desipramine was determined in vitro. The PKC activity of the major depressive disorder subjects and healthy volunteers was inhibited by desipramine, whereas that of the bipolar disorder subjects showed both inhibition and activation. In addition, the base PKC activity incubation with antidepressants of the major depressive disorder patients was significantly higher than of the

bipolar disorder patients. These preliminary results suggest that the function of PKC may, at least in part, be associated with the mechanism of affective disorder.

Publication Types:
• Clinical Trial
• Controlled Clinical Trial

PMID: 10201278 [PubMed - indexed for MEDLINE]
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COMMENT FROM DEB: Again, the above abstracts indicate dose of desipramine is probably important, but that the correct dose DOES inhibit PKC activity, which stimulates axon growth after injury. (All I can do right at the moment myself, based on my own improvement – twice – is to purely guess that a lower dose of desipramine is the best for all of these proposed “theories” that I’ve been putting together.) More testing should be done regarding desipramine’s actions on PKC, because I couldn’t find too much on this, but the evidence of beneficial action is certainly there in my opinion. (Plus, I’m factoring in all of the other correlations of desipramine that I’ve found so far, and my own neurological improvement, when it comes to dosage).

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J Neuroimmunol. 2003 Dec;145(1-2):139-47.
Related Articles, Links

Serum and cerebrospinal fluid antibodies to Nogo-A in patients with multiple sclerosis and acute neurological disorders.

Reindl M, Khantane S, Ehling R, Schanda K, Lutterotti A, Brinkhoff C, Oertle T, Schwab ME, Deisenhammer F, Berger T, Bandtlow CE.

Department of Neurology, University of Innsbruck, Anichstrasse 35, Innsbruck, 6020, Austria. markus.reindl@uibk.ac.at

Nogo-A is a protein associated with central nervous system (CNS) myelin thought to impair regenerative responses and to suppress sprouting and plastic changes of synaptic terminals. In this study, we report that serum IgM autoantibodies to the recombinant large N-terminal inhibitory domain of Nogo-A are a frequent finding in multiple sclerosis (MS) and acute inflammatory (IND) and non-inflammatory neurological diseases (OND), but not in neurodegenerative diseases (ND), systemic inflammatory disease and healthy controls. Furthermore, we demonstrate intrathecal production of anti-Nogo-A antibodies measured by increased IgG indices. Intrathecal anti-Nogo antibodies were significantly more frequent in patients with relapsing-remitting as compared to chronic progressive (CP) MS. We also found a highly significant negative correlation of these antibody responses with age indicating that they are more frequent in younger patients. We finally demonstrate that human anti-Nogo-A antibodies recognize native Nogo-A in brain extracts, oligodendrocytes and cells expressing human Nogo-A.

PMID: 14644040 [PubMed - indexed for MEDLINE]
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COMMENT FROM DEB: Well, Nogo and its implications with MS is a newly talked about discovery, and it appears yet again, that we have some correlations of desipramine’s beneficial interactions with Nogo (inhibition – which is what we want) via the PKC pathway, and the above abstract also just provides a more direct correlation with MS.

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: J Neurosci. 2004 Feb 18;24(7):1646-51. Related Articles, Links

Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state.

Fischer D, He Z, Benowitz LI.

Department of Neurosurgery, Children's Hospital Boston, Massachusetts 02115, USA.

Mature retinal ganglion cells (RGCs), like other CNS neurons, cannot regrow injured axons into a myelin-rich environment. If stimulated by macrophage-derived factors, however, RGCs can regenerate their axons for considerable distances through the distal optic nerve. Using this "sensitized background," we investigated the effects of either increasing the expression or suppressing the activity of the Nogo receptor (NgR). NgR mediates the growth-inhibiting effects of three myelin proteins, Nogo, OMgp (oligodendrocyte-myelin glycoprotein), and MAG (myelin-associated glycoprotein). Transfecting growth-sensitized RGCs with adeno-associated viruses expressing a dominant-negative form of NgR (NgR(DN)) increased axon regeneration several-fold; however, when the growth program of RGCs was not activated, NgR(DN) expression had no beneficial effects. Overexpression of wild-type NgR blocked almost all regeneration from growth-sensitized RGCs and caused axons proximal to the lesion site to retract. We conclude that gene therapy is an effective approach to enhancing axon regeneration in the CNS and that inactivation of NgR functioning greatly enhances axon regeneration provided the intrinsic growth program of neurons is activated.

PMID: 14973241 [PubMed - indexed for MEDLINE]
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COMMENT FROM DEB: Well, we don’t need to rehash the fact that desipramine (and levetiracetam) help to activate growth neurons, GAP43, and neurotrophins (increased BDNF is an integral one), not to mention desipramine’s effects on cyclic AMP (as mentioned previously, also). And, somehow desipramine must cross over the invisible line a bit from being simply a TCA to directly affecting mitochondia, etc., so also MIGHT be considered something of a mild “gene therapy”? I did originally speculate something to that affect in my original research by associating desipramine’s mechanisms of action to being similar to a TZD (gene therapy). (Hey, maybe I’m not as dumb as I look after all! Problem was back then, i.e. a few months ago, I was running more on intuition than facts! It’s hard to prove intuition.)

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: J Neurosci. 2003 May 15;23(10):4219-27. Related Articles, Links

Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury.

Li S, Strittmatter SM.

Department of Neurology and Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Traumatized axons possess an extremely limited ability to regenerate within the adult mammalian CNS. The myelin-derived axon outgrowth inhibitors Nogo, oligodendrocyte-myelin glycoprotein, and myelin-associated glycoprotein, all bind to an axonal Nogo-66 receptor (NgR) and at least partially account for this lack of CNS repair. Although the intrathecal application of an NgR competitive antagonist at the time of spinal cord hemisection induces significant regeneration of corticospinal axons, such immediate local therapy may not be as clinically feasible for cases of spinal cord injury. Here, we consider whether this approach can be adapted to systemic therapy in a postinjury therapeutic time window. Subcutaneous treatment with the NgR antagonist peptide NEP1-40 (Nogo extracellular peptide, residues 1-40) results in extensive growth of corticospinal axons, sprouting of serotonergic fibers, upregulation of axonal growth protein SPRR1A (small proline-rich repeat protein 1A), and synapse re-formation. Locomotor recovery after thoracic spinal cord injury is enhanced. Furthermore, delaying the initiation of systemic NEP1-40 administration for up to 1 week after cord lesions does not limit the degree of axon sprouting and functional recovery. This indicates that the regenerative capacity of transected corticospinal tract axons persists for weeks after injury. Systemic Nogo-66 receptor antagonists have therapeutic potential for subacute CNS axonal injuries such as spinal cord trauma.

PMID: 12764110 [PubMed - indexed for MEDLINE]

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COMMENT FROM DEB: The above was just more substantiation regarding Nogo, and introduces a time factor regarding axonal repair.

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COMMENT FROM DEB: Pasted below is just an internet address to an article that sort of uncannily brings all of the above factors into one, and also mentions Rho, which brings us full circle again back to the very first article I pasted in this! And again, compared with my previous and current findings on desipramine’s actions, well need I say more?

http://molinterv.aspetjournals.org/cgi/ ... ll/2/4/244


AS AN ASIDE, HERE ARE SOME INTERESTING THINGS REGARDING NOREPINEPHRINE AND THE PATHOGENESIS OF MS THAT GOT ME MOTIVATED INITIALLY TO KEEP RESEARCHING!:

This article is one I referred to in my first research paper:

Neurobiol Dis. 2004 Mar;15(2):331-9. Related Articles, Links

Astrocytic beta2-adrenergic receptors and multiple sclerosis.

De Keyser J, Zeinstra E, Wilczak N.

Department of Neurology, University Hospital Groningen, Groningen, The Netherlands. j.h.a.de.keyser@neuro.azg.nl

Despite intensive research, the cause and a cure of multiple sclerosis (MS) have remained elusive and many aspects of the pathogenesis are not understood. Immunohistochemical experiments have shown that astrocytic beta(2)-adrenergic receptors are lost in MS. Because norepinephrine mediates important supportive and protective actions of astrocytes via activation of these beta(2)-adrenergic receptors, we postulate that this abnormality may play a prominent role in the pathogenesis of MS. First, it may allow astrocytes to act as facultative antigen-presenting cells, thereby initiating T-cell mediated inflammatory responses that lead to the characteristic demyelinated lesions. Second, it may contribute to inflammatory injury by stimulating the production of nitric oxide and proinflammatory cytokines, and reducing glutamate uptake. Third, it may lead to apoptosis of oligodendrocytes by reducing the astrocytic production of trophic factors, including neuregulin, nerve growth factor and brain-derived neurotrophic factor. Fourth, it may impair astrocytic glycogenolysis, which supplies energy to axons, and this may represent a mechanism underlying axonal degeneration that is hold responsible for the progressive chronic disability.

Publication Types:
• Review
• Review, Tutorial

PMID: 15006703 [PubMed - indexed for MEDLINE]

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Am Surg. 2004 Jun;70(6):526-8. Related Articles, Links

Norepinephrine is a more potent inhibitor of tumor necrosis factor over a range of doses than dopamine.

Morgan JH 3rd, Gamblin TC, Adkins JR, Groves JR, Dalton ML, Ashley DW.

Department of Surgery, Medical Center of Central Georgia, Mercer University School of Medicine, Macon, Georgia 31201, USA.

In the current study, we test the hypothesis that norepinephrine has greater anti-inflammatory effects versus dopamine over a range of doses in a model of lipopolysaccharide (LPS)-stimulated cytokine release in human saphenous vein. Segments of saphenous vein were cut and separated into 1 mm x 1 mm squares and placed into two 24-well plates. These small segments of vessels were incubated in the presence of 20 microg/mL bacterial LPS, alone as a control or with 10x-6, 10x-5, 10x-4, 10x-3 concentration of dopamine or norepinephrine and LPS. The general linear models (GLM) statistical analysis for least squares means and adjustment for multiple comparisons was chosen to analyze the data. Both norepinephrine and dopamine were able to suppress the production of tumor necrosis factor (TNF) in a dose-dependent fashion. Over the range of doses, norepinephrine is a more potent inhibitor of TNF production than dopamine. This is a statistically significant linear trend (P < .0001). Both norepinephrine and dopamine are powerful anti-inflammatory agents. Norepinephrine is a more potent inhibitor of TNF than dopamine.

PMID: 15212408 [PubMed - in process]

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Mult Scler. 2004 Apr;10(2):165-9. Related Articles, Links

Cytokine mRNA expression in patients with multiple sclerosis and fatigue.

Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, Rieckmann P.

Department of Neurology, Julius-Maximilians University of Wurzburg, Josef-Schneider-Strasse 11, D-97080 Wurzburg, Germany. peter.flachenecker@surfeu.de

BACKGROUND: Fatigue is one of the most common disabling symptoms in patients with multiple sclerosis (MS), but the putative role of proinflammatory cytokines remains to be elucidated. METHODS: Thirty-seven patients (27 women, 10 men) with relapsing remitting (n = 29) and secondary progressive (n = 8 ) MS, aged 41.0 +/- 10.2 years, were studied. Fatigue was assessed by Krupp's Fatigue Severity Scale (FSS). Cytokine mRNA expression for interferon (IFN)-gamma tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were measured by real time RT PCR. Autonomic function was evaluated by standard tests for parasympathetic and sympathetic function, as well as by serum levels of norepinephrine and epinephrine. RESULTS: Median levels of TNF-alpha mRNA expression were significantly higher in MS patients with (FSS > or = 4.0 and > or = 5.0, n = 26 and n = 14, respectively) than in those without fatigue (FSS < 4.0, n = 11). No differences were seen for IFN-gamma and IL-10 mRNA expression. Cytokine levels were not correlated to autonomic tests or to serum catecholamine levels. CONCLUSIONS: These results suggest that TNF-alpha, as a principal proinflammatory mediator, is associated with MS-related fatigue. This is in support of a pathogenic role of the MS-related inflammatory process in the development of fatigue.

PMID: 15124762 [PubMed - indexed for MEDLINE]

COMMENT FROM DEB: REDUCE TNFa AND YOU HELP MS RELATED FATIGUE? THIS IS A NEW ONE FOR ME, EVEN. AND INCREASING NOREPINEPHRINE HELPS THAT, AS SHOWN PREVIOUSLY ABOVE.

THAT'S ALL FOLKS! If you made it this far, thank you for your time and interest! All the best,

Deb

There has been a lot of talk about Dr. Sriram and his research into chlamydia pneumoniae (hereinafter called CP) in connection to MS. I know there are conflicting theories as to whether this will be a dead end or not, and that's ok. Whatever. Here's the thing, though. I thought, ok......I'll become more familiar with this theory.

Again, even with Dr. Sriram's research, it is geared mainly toward RRMS, and he himself has made comments regarding how little is known about CP with regard to progressive MS and axonal damage or regeneration. And he makes mention of how he suspects, perhaps, that antibiotic treatment for CP in progressive MS may not prove itself to be effective, so he's concentrating on RRMS.

Just for kicks and giggles, as I say, I thought, ok.....let's see what might counteract any negative effects if CP is found to be "aggravating" MS and/or axonal degeneration. Rumor has it (posted below) that controlling the influx of Ca2 is quickly proving itself to be integral in controlling CP's damaging affects. I'm sorry, at this point, I started to laugh.

I JUST posted documentation on my theories about how desipramine helps to control the influx of Ca2, without even realizing any connection whatsoever with CP! Again, I'm making this connection also directly to helping progressive MS and preventing/correcting axonal damage.

In addition, there is mention of IL1b and inflammation with CP, also, which again, I won't go into how desipramine lowers IL1b and its beneficial effects on anti-inflammatory processes. (And APCs, etc.) It all just goes round and round.

So.....to make a possible long story short, I will just say to add this to the
mounting evidence of desipramine's probable beneficial effects for progressive MS, IF given at the right dosage and used very carefully in combination therapy.

Personally, which is neither here nor there, I believe that they will eventually find CP to be just another "aggravation" sometimes, but not a cause.

Deb

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Med Microbiol Immunol (Berl). 2004 Jun 12 [Epub ahead of print] Related
Articles, Links

Elicitation of reactive oxygen species in Chlamydia pneumoniae-stimulated macrophages: a Ca(2+)-dependent process involving simultaneous activation of NADPH oxidase and cytochrome oxidase genes.

Azenabor AA, Yang S, Job G, Adedokun OO.

Department of Health Sciences, Enderis Hall, University of Wisconsin, Room 469,
2400 E. Hartford Avenue, WI 53211, Milwaukee, USA.

Chlamydia pneumoniae, a respiratory pathogen implicated in the development and progress of atherosclerosis, is known to infect and survive in macrophages, despite macrophage producing reactive oxygen species (ROS). To gain insight into ROS generation in macrophages infected with C. pneumoniae and to explore factors accounting for their final levels and effect, we investigated the role of NADPH oxidase and cytochrome oxidase pathways in the production and modulation of ROS.
We also determined the operational role of Ca(2+) signaling in the process.
Macrophages stimulated with C. pneumoniae exhibit early release of ROS via up-regulation of NADPH oxidase and cytochrome c oxidase activities. Increasing the dose of C. pneumoniae led to an increase in the expression of these enzymes' gene production, which was accompanied by a significant up-regulation of their gene products, implying a probable activation of transcriptional and translational processes, respectively. The change in levels of free Ca(2+), influx across plasma membrane and efflux from intracellular store into cytosol all exhibited a significant regulatory role on the ROS generation pathways in macrophages. The observed events were shown to be dependent on binding of C.
pneumoniae to CD14 receptors of macrophages. The data reported here imply that macrophages infected with C. pneumoniae produce ROS through membrane-associated NADPH oxidase with oxidative phosphorylation levels depending on Ca(2+) influx signals.

PMID: 15197588 [PubMed - as supplied by publisher]
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Biol Chem. 2004 Jan;385(1):67-74. Related Articles, Links

Induction of lipoprotein lipase gene expression in Chlamydia pneumoniae-infected macrophages is dependent on Ca2+ signaling events.

Azenabor AA, Job G, Yang S.

Department of Health Sciences, University of Wisconsin, 2400 E. Hartford Avenue, Milwaukee, WI 53211, USA. aazenabo@uwm.edu

Unregulated uptake of low density lipoprotein (LDL) in macrophages is the
hallmark of early atherogenic lesions, and Chlamydia pneumoniae infection of macrophages induces this process by an unknown mechanism. It was therefore aimed in this study to investigate (i) the role of C. pneumoniae in macrophage expression of the lipoprotein lipase (LpL) gene, (ii) the probable role of Ca2+ influx signals and (iii) the effect of the process on LDL uptake. Lipoprotein lipase mRNA expression and LpL activity in infected RAW-264.7 cells were significantly upregulated. A biphasic Ca2+ influx signal was observed in infected cells with a moderate influx (303 nM Ca2+) favoring optimal LpL gene expression. Also, the antagonists of L-type Ca2+ channel in macrophages
significantly down-regulated LpL gene expression and the biomolecular content of C. pneumoniae responsible for the observed events was in part found to be Chlamydia lipopolysaccharide (cLPS). Investigations aimed at determining the specific relevance of Ca(2+)-dependent lipoprotein lipase gene expression in C. pneumoniae-infected macrophages showed that the condition caused enhanced uptake of LDL which was abrogated by Calphostin-C-mediated down-regulation of LpL. This discovery of a specialized Ca2+ influx signal-mediated LpL upregulation in C.
pneumoniae-infected macrophages provides a mechanistic insight into early events involving C. pneumoniae in macrophage foam cell formation resulting from LDL uptake.

PMID: 14977048 [PubMed - in process]
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: Immunobiology. 2003;207(4):237-45. Related Articles, Links

Macrophage L-type Ca2+ channel antagonists alter Chlamydia pneumoniae MOMP and HSP-60 mRNA gene expression, and improve antibiotic susceptibility.

Azenabor AA, Chaudhry AU, Yang S.

Department of Health Sciences, University of Wisconsin, Milwaukee, WI 53211, USA. aazenabo@uwm.edu

Recent data have shown a unique relationship between Ca2+ signaling in
macrophages through L-type channels and the outcome of C. pneumoniae infection of such cells. The present investigation seeks to provide insights into the manner in which macrophage L-type Ca2+ channel operation affects major outer membrane protein (MOMP) and heat shock protein-60 (HSP-60) mRNA gene expression (factors associated with Chlamydia chronicity), and the possible effect of this on antibiotic susceptibility. Intracellular calcium ([Ca2+]i) chelation using varying doses of 1,2-bis (o-aminophenoxy) ethane-N,N,N'N'--tetra acetic acid (acetoxymethyl) ester (BAPTA-AM) induced an increase in MOMP and a decrease in
HSP-60 mRNA gene expression. L-type Ca2+ channel antagonists produced an identical but enhanced effect. Since these findings associate specialized Ca2+ channels to Chlamydia chronicity, it was important to determine Ca2+ channel effect on the usual antibiotic refractory form of C. pneumoniae in macrophages. Inhibition of macrophage L-type Ca2+ channel operation improved C. pneumoniae antibiotic susceptibility assessed by decreased inclusion counts or down-regulated MOMP and HSP-60 mRNA gene expression. These findings provide molecular insights into how specialized Ca2+ channels influence Chlamydia chronic course in macrophages and demonstrates a role for L-type Ca2+ channel inhibitors in enhanced C. pneumoniae susceptibility to antibiotic therapy.

PMID: 12952346 [PubMed - indexed for MEDLINE]
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Eur Respir J. 2003 Aug;22(2):274-9. Related Articles, Links

Imbalanced secretion of IL-1beta and IL-1RA in Chlamydia pneumoniae-infected mononuclear cells from COPD patients.

Rupp J, Kothe H, Mueller A, Maass M, Dalhoff K.

Institute of Medical Microbiology and Hygiene, University of Lubeck, Lubeck, Germany. jan.rupp@hygiene.ukl.mu-luebeck.de

Balanced secretion of pro- and anti-inflammatory cytokines is essential in
limiting pulmonary inflammation in respiratory infections. It was hypothesised that, in acute infection with Chlamydia pneumoniae, mononuclear cells from chronic obstructive pulmonary disease (COPD) patients lack the opportunity to compensate for the inflammatory immune response by secreting adequate amounts of anti-inflammatory cytokines. Alveolar macrophages (AMs) and peripheral blood mononuclear cells (PBMCs) from eight COPD patients and eight healthy controls were infected with C. pneumoniae in order to determine interleukin (IL)-1beta,
IL-1 receptor antagonist (IL-1RA) and IL-8 expression and messenger ribonucleic acid levels. Secretion of IL-1beta was significantly enhanced in AMs (six-fold) and PBMCs (four-fold) from COPD patients after infection with C. pneumoniae. Compared to the control group, release of its anti-inflammatory counterpart IL-1RA was diminished in COPD patients, resulting in a significantly higher IL-1beta/IL-1RA ratio in C. pneumoniae-infected AMs and PBMCs from COPD patients. Mononuclear cells from chronic obstructive pulmonary disease patients have less capacity for balancing the pro-inflammatory immune response caused by Chlamydia pneumoniae infection than those from healthy controls. These findings suggest that, during acute exacerbation with intracellular pathogens, chronic obstructive pulmonary disease patients are predisposed to inflammatory changes in the lungs.

PMID: 12952260 [PubMed - indexed for MEDLINE]