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Chronic
Inflammation

 

CLL, Chronic Inflammation and What You Can Do About It

November 15, 2003

by Chaya Venkat

Civilization is a very recent phenomenon in the history of Man, and in some important ways it has turned our very bodies against us. Even just a couple of generations back, the main cause of death was infections of various sorts. Millions of years of evolution and genetic selection has seen to it that we have very alert and powerful immune systems, a trigger happy immune defense mechanism was a matter of survival. But modern babies raised on the tenets of "Childcare by Dr. Spock" see very few pathogens in their sterilized and ultra clean surroundings. Have you heard the phrase "idle hands are the devil's workshop"? Our immune systems have much less to do than they were designed for, and in the process of making work for themselves, they sometimes go more than a little crazy, with serious consequences.

We are all familiar with the signs of inflammation, the redness, pain and heat generated at the site of a cut, or an insect bite. Under normal circumstances, this is a good thing. When the ever vigilant cells of the immune system find an enemy, they rush to attack and release powerful chemical signals attracting more troops to that location. But too much of a good thing can be bad for you sometimes the chemical alarm goes off even when there is no enemy to fight and does not switch itself off after a decent interval. This is chronic inflammation, and today it is recognized to be the cause of many diseases. The short list of diseases that can be aided and abetted by chronic inflammation include cancer, autoimmune diseases like lupus, MS, rheumatoid arthritis, Crohn's disease, autoimmune diabetes, cardiovascular disease and Alzheimer's disease, just to name a few. I think you get the picture, chronic inflammation is no small problem and it is certainly an issue for CLL patients. We have discussed several aspects of inflammation as it pertains to CLL, such as Cox-1 and Cox-2 in other articles. This article focuses on one specific aspect of chronic inflammation that seems to have been recently discovered and very intriguing connections to CLL.

Compounds called cysteinyl leukotrienes (CysLTs) are important mediators of inflammation. Once synthesized, leukotrienes exert very powerful pro-inflammatory effects such as those seen asthma, wheezing, bronchial spasms, mucus formation, sinusitis, etc. We will focus on just one of the leukotrienes, called LTD4. Before moving on to CLL, let us see what happens in an asthmatic episode. LTD4 is formed as part of the inflammatory process and it is found liberally in the lungs and associated airways. Cells that have the right receptor (called CysLT1) that mates with LTD4 are attracted to the site. Among these are various immune system cells such as monocytes, eosinophils and macrophages. Drawn by the siren call of LTD4, these immune system cells congregate in great numbers in the lungs. Mating of the LTD4 with the right receptors on the immune system cells causes production of more LTD4, which then attracts even more immune system cells and so on. This creates a snowball effect, quickly getting out of control. Cutting through a great deal of very complex biochemistry, here is the bullet-point version of how all this impacts CLL patients.

LTD4 Receptors on Human Immune System Cells.

Figeroa, Breyer, et. al.
Am. J. Respir. Crit. Care Med., Volume 163, Number 1, January 2001, 226-233
 

 

  • LTD4 is present not just in lung and airways muscle tissue, but also in the lymph nodes and bone marrow, and chronic inflammation increases these levels.

  • Here is the punch line, CLL cells are now shown to have an unhealthy level of the receptor capable of mating with LTD4.

  • Responding to the chemical signal of LTD4, CLL cells follow the bread crumb trail to the lymph nodes, spleen and bone marrow. This may explain why CLL cells congregate in these areas, rather than sloshing around in the peripheral blood.

  • Interaction between the LTD4 and its receptors on CLL cells creates the microenvironment that is just right for the CLL cells, making them harder to kill, and helping them proliferate. Does this explain to some degree why it is so much harder to clear out bone marrow and lymph nodes during therapy, compared to the cancer cells in the peripheral blood?

  • Sure, the receptors on CLL cells also interact with the LTD4 in lungs and airways. Is this why pneumonia is such a common occurrence in CLL, one of the major causes of death? Is the bacterial infection something that happens when bacteria colonize and thrive in the heavy mucus produced as a result of the inflammatory responses of activated CLL cells interacting with LTD4?

  • Does the mating of the LTD4 and its receptors of CLL cells also explain the very frequent sinus problems that plague many CLL patients?

  • Men have a higher expression of the LTD4 receptor than women. Does this explain why CLL strikes men more often than women?

  • Mating between LTD4 and its receptors on CLL cells is accompanied by calcium ions coming out of the cells of the muscle tissue carrying the LTD4. Calcium balance is very important in proper functioning of muscle cells. Imbalance in calcium ions can cause strong involuntary muscle contractions, similar to bronchial spasms experienced by asthmatic patients. Does this effect also explain the muscle cramps suffered by many late stage CLL patients?

  • One of the B-symptoms we are told to watch for is fatigue and tiredness. As CLL progresses, we know that the bone marrow is less able to produce all the necessary cell lines. Red blood cells are essential for carrying oxygen from the lungs to each and every part of our body. As red blood cell counts decline, and anemia sets in, it is easy to understand that the body is gradually starved for oxygen, and we get tired easily. Can this be aggravated and made worse by chronic inflammation of the lungs and associated airways, perhaps clogged with mucus generated by LTD4 interacting with its receptors on CLL cells?

If you have been a patient reader and waded through all this strange stuff, here is your reward, some practical things that you could discuss with your doctor. A number of very specific and low-toxicity drugs have been approved by the FDA for use in controlling asthma. These drugs work by blocking the receptors for LTD4. Two well known ones are "Singulair" ('montelukast' - Merck & Co.), and "Accolate" ('zafirlukast' - Zeneca Pharmaceuticals). A third one "Ultair" ('pranlukast' - SmithKline Beecham) has been approved in Europe and Japan, and is in late stage trials in this country.

  • The ASH 2003 abstract below spells it out quite explicitly. Since CLL cells exhibit the LTD4 receptor, there is reason to hope that drugs such as Singulair and Accolate will work on them as well, blocking the receptors. (The ASH abstract uses the correct name "CysLT1" to refer to the receptor for LTD4. Don't let that confuse you).

  • With their LTD4 receptors blocked, CLL cells may not follow the chemical trails attracting them to the lymph nodes and bone marrow. Lower bone marrow infiltration by CLL cells means more room for the bone marrow to produce all the other cell lines it has to produce. Smaller lymph nodes are good news, since bulky lymph nodes are the hardest to treat and clean out by most therapy choices.

  • Without the supportive microenvironment built in the bone marrow and lymph nodes by the interaction between LTD4 and its receptors on CLL cells, the single roving CLL cells are easier to kill, and they do not proliferate as fast. Bottom line, a less aggressive disease, and more easily handled by less toxic therapy choices.

  • Blocking the LTD4 receptors on CLL cells may keep a lid on constant sinus problems, potential lung disease, and may reduce muscle spasms and cramps. Better oxygen exchange capacity in the lungs may reduce the fatigue and tiredness generally associated with anemia in progressed CLL.

Singulair and Accolate have been mentioned in several patient groups as potential approaches to reducing the rate of progression of CLL. We may now have a better understanding of the connection between these two drugs (and the third one 'pranlukast' mentioned in the ASH abstract below) and their ability to control chronic inflammation. While these drugs have been approved for asthma, it seems that there may be a common thread of chronic inflammation that works both in asthma as well as in CLL progression. Since these LTD4 receptor blockers have a track record of well documented low toxicity, this may be an interesting approach to pursue in reducing the rate of progression of CLL in early stage patients, as well as potentially prolong remissions after therapy; in other words, these commercially available and low-toxicity drugs may be one component of the third leg of our beloved "Project Alpha".

LTD4 receptor blockers are certainly something worth discussing with your doctors, in the opinion of this lay person reporter.

Abstracts:

1601] The Leukotriene Receptor CysLT1 Is Involved in Migration and Survival of Chronic Lymphocytic Leukemia (CLL) Cells: Potential Role of CysLT1Antagonists in the treatment of CLL

Andreas M. Boehmler, Gabriele Seitz, Tina Wiesner, Lothar Kanz, Robert Mhle Department of Medicine II, University of Tbingen, Tbingen, Germany

G protein-coupled receptors (GPR) mediate chemotactic and proliferative effects in both normal and malignant hematopoietic cells. CysLT1, a GPR for a subgroup of lipid mediators (cysteinyl-leukotrienes), is involved in inflammatory reactions such as allergic asthma, but its ligands are also released in the bone marrow by stromal and endothelial cells similar to the chemokine SDF-1. In RT-PCR analyses, we now demonstrate expression of CysLT1 in the CLL cell lines EHEB and MEC-1, as well as in CD19+ cells isolated immunomagnetically from the peripheral blood of patients with B-CLL. Stimulation of CLL cells with the natural CysLT1 ligand cysteinyl leukotriene D4 (LTD4) resulted in a sustained effect on the cytoskeleton with a 37.8% increase in the concentration of filamentous actin. In transmigration experiments throughfenestrated polycarbonate membranes (pore size: 5 M), CLL cells responded positively chemotactic to LTD4, with an increase in the total number of transmigrated cells of up to 6-fold as compared to carrier alone. In addition, the CysLT1 receptor antagonist MK-571 drastically decreased the in vitro survival of primary CLL cells as well as of CLL cell lines. Interestingly, antiproliferative effects were seen at receptor antagonist concentrations (low micromolar), which could potentially be achieved by oral treatment in vivo. We conclude that expression of CysLT1 may contribute to bone marrow tropism of CLL cells and their maintenance in the hematopoietic microenvironment. More important, the highly antiproliferative effect of CysLT1 receptor antagonists, which are currently used only in asthma therapy, might offer a new approach in the therapy of CLL.

Abstract #1601, ASH 2003
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Curr Opin Otolaryngol Head Neck Surg. 2003 Jun;11(3):184-91.

The role of leukotriene inhibitors in patients with paranasal sinus disease.

Parnes SM.

Department of Surgery, Division of Otolaryngology, Albany Medical College, Albany, New York, USA.

Leukotrienes are inflammatory mediators that are known as the slow-reacting substance of anaphylaxis produced by a number of cell types including mast cells, eosinophils, basophils, macrophages, and monocytes. Synthesis of these mediators results from the cleavage of arachidonic acid in cell membranes, and they exert their biologic effects by binding and activating specific adaptors. This occurs in a series of events that lead to contraction of the human airway smooth muscle, chemotaxis, and increased vascular permeability. These effects have led to their important role in the diseases of asthma, allergic rhinitis, and possible paranasal sinusitis with the formation of nasal polyps. Because these agents lead to the production of symptoms in patients that are asthmatic, the use of leukotriene enzyme inhibitors, particularly montelukast, and zafirlukasts seem appropriate. These classes of drugs can block the binding of leukotrienes to CysLT(1) receptors. Zileuton is a 5-lipoxygenase inhibitor that prevents the formation of leukotrienes and can also result in the prevention of leukotriene activity. Demonstrated efficacy in these patients in a number of studies has also suggested their role in inhibiting nasal symptoms in asthmatic patients. In addition, it has been suggested by serendipitous observations that many of the aspirin-intolerant patients have nasal polyps and that treatment with the leukotriene inhibitors has resulted in improvement and resolution of the polyps. Therefore, these agents may also play a role in patients afflicted with chronic sinusitis with concomitant nasal polyposis. These papers are discussed in detail because this form of therapy may represent a novel way to treat patients with this malady in addition to or in lieu of surgical treatment and steroid therapy.

PMID: 12923360
______________

Gastroenterology. 2003 Jan;124(1):57-70.

Expression of the leukotriene D4 receptor CysLT1, COX-2, and other cell survival factors in colorectal adenocarcinomas.

Ohd JF, Nielsen CK, Campbell J, Landberg G, Lofberg H, Sjolander A.

Division of Experimental Pathology, Department of Laboratory Medicine, Malmo University Hospital, Lund University, SE-205 02 Malmo, Sweden.

BACKGROUND & AIMS: The effects of leukotriene (LT) D(4) on intestinal epithelial cells govern events that are involved in cell survival and colon cancer, notably increased expression of cyclooxygenase (COX)-2 and enhanced production of prostaglandin E(2). We investigated possible correlations between distribution of the recently described LTD(4) receptor CysLT(1)R and factors previously shown to be up-regulated by LTD(4) as well as clinicopathologic traits.
METHODS: Immunohistochemistry and in situ hybridization were performed on tissue arrays, which were made using colorectal cancer samples from 84 patients.
RESULTS: CysLT(1)R was significantly correlated to COX-2, 5-lipoxygenase, and Bcl-x(L). Male subjects more often exhibited high levels of this receptor relative to female subjects, and Dukes' B patients with elevated CysLT(1)R expression showed markedly poorer survival than those with low-level expression. Furthermore, this was paralleled by an increased viability of CysLT(1)R-overexpressing cells in a colon cancer cell line.
CONCLUSIONS: Our results further implicate the involvement of LTs in colorectal carcinoma. Based on our present and earlier findings, we propose that LT/CysLT(1)R signaling facilitates survival of colon cancer cells, which may affect disease outcome. Like COX-2, LTs are accessible targets for pharmacologic treatment.

PMID: 12512030
______________

Am. J. Respir. Crit. Care Med., Volume 163, Number 1, January 2001, 226-233

Expression of the Cysteinyl Leukotriene 1 Receptor in Normal Human Lung and Peripheral Blood Leukocytes

Figueroa DJ, Breyer RM, Defoe SK, Kargman S, Daugherty BL, Waldburger K, Liu Q, Clements M, Zeng Z, O'Neill GP, Jones TR, Lynch KR, Austin CP, Evans JF.

Department of Nephrology, Vanderbilt University, Nashville, Tennessee; Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, Virginia; Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania; Department of Biochemistry and Molecular Biology, Merck Frosst Canada Inc., Dorval, Quebec, Canada; and Department of Immunology, Merck Research Laboratories, Rahway, New Jersey

The cysteinyl leukotrienes (CysLTs) are important mediators of human asthma. Pharmacologic and clinical studies show that the CysLTs exert most of their bronchoconstrictive and proinflammatory effects through activation of a putative, 7-transmembrane domain, G-protein-coupled receptor, the CysLT1 receptor. The initial molecular characterization of the CysLT1 receptor showed by in situ hybridization, the presence of CysLT1 receptor messenger RNA (mRNA) in human lung smooth-muscle cells and lung macrophages. We confirmed the results of these in situ hybridization analyses for the CysLT1 receptor, and produced the first immunohistochemical characterization of the CysLT1 receptor protein in human lung. The identification of the CysLT1 receptor in the lung is consistent with the antibronchoconstrictive and antiinflammatory actions of CysLT1 receptor antagonists. We also report the expression of CysLT1 receptor mRNA and protein in most peripheral blood eosinophils and pregranulocytic CD34+ cells, and in subsets of monocytes and B lymphocytes.

Link: http://ajrccm.atsjournals.org/cgi/content/full/163/1/226.

PMID: 11208650
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