Sunday, May 21, 2017

The macrophage: A high-tech micro vacuum cleaner.

Do you have a vacuum cleaner? Maybe you call it a Hoover, after the inventor? And do you use it?
If yes, you might be a woman. Anyway, being a man myself, my first vacuum cleaner entered my life after my marriage. Before that time, I did wait until the dust under my bed had produced a solid carpet there. Once a year, I rolled it up and threw it in the dust-bin.
As you understand, I am a lazy man, so the only suitable profession for me would be scientific research. There are few other possibilities to spend nearly all of your time on thinking. If doing would become an inevitable consequence, many nice students and/or technicians will help you to overcome this barrier.

I have several problems with a vacuum cleaner.
First of all, it produces a lot of noise, disturbing thinking.
Secondly, a vacuum cleaner is nowadays an old-fashioned apparatus. You have to control its activities and to check where it did remove dust and where not. This is especially tiring if you do not see any dust on places where others obviously see a lot of it.
A modern vacuum cleaner, adapted to our time, should have the following characteristics:
1. It should work without your own control. If your string of pearls is broken, the pearls should not be sucked together with the real dust by the apparatus. In other words, it should be able to discriminate. Contrary to a police officer, a vacuum cleaner would be praised for this capability.
2. Before the battery would be dead, the apparatus should be able to charge itself again.
3. The apparatus should be able to recycle the ingested dust in order to reuse it subsequently for a useful purpose.
4. The apparatus should be able to control and regulate several other functions in your house. If it becomes dark, the lights have to be turned on and the curtains have to be closed by the apparatus via remote control.
5. If more activity would be required somewhere, the apparatus should be able to replicate itself and the copies should be able to collaborate in the job.

As you will know, many human inventions are based on observations in nature. In the present case, we should focus on a micro vacuum cleaner, the macrophage, a cell present in nearly all tissues of our body.
From an evolutionary point of view, macrophages are ancient cells. They form the core of the natural immune system and did appear long before the cells forming together the complex immune system of the higher vertebrates to which we belong.
Macrophages are involved in "homeostasis" of the body by ingesting and digesting microorganisms or other non-self particles as well as products of inflammation or immune reactions, such as macromolecules or antibody-complexed antigens.
Intracellular digestion is mediated by their panels of lysosomal enzymes. As a consequence large concentrations of materials such as amino-acids for the building of new proteins are available.
During evolution, macrophages did acquire functions in the regulation of several other cells in the body. Differentiation, maturation, migration and/or functioning of these non-phagocytic cells could be stimulated or inhibited by soluble mediator molecules, such as cytokines and chemokines, produced and released by macrophages in the circulation and/or body fluids. They will act as a remote control system.

Their functions could be studied with the help of an approach to deplete macrophages selectively from tissues and/or organs in the body. By this approach, i.e. by creating an animal with macrophage-depleted tissues or organs - dependent on the administration route of the liposomes - functional aspects of macrophages could be studied "in vivo".
Liposomes - artificially prepared inert vesicles, consisting of concentric phospholipid bilayers, separated by aqueous compartments - will be eagerly swallowed by macrophages and will be subsequently digested with the help of their phospholipase enzymes.
Liposomes as structures were discovered by Alec Bangham (UK, died on March 9, 2010). He found that amphipathic phospholipid molecules, dispersed in water, became organised in vesicles, consisting of concentric phospholipid bilayers, separated by aqueous compartments. The hydrophobic fatty acid chains of each part of the bilayers were opposed to each other, whereas the hydrophilic head groups of the fatty acids were exposed to the water compartments separating the individual bilayers.
Hydrophilic molecules solved in the aqueous solution, used for preparation of the liposomes, could be entrapped into the aqueous compartments between the phospholipid bilayers and it was Gregory Gregoriadis (Greece/UK), who proposed and formulated liposomes as carriers of drugs in biology and medicine, i.e. the liposomal drug carrier concept.
Clodronate (dichloromethylene bisphosphonate) is a member of the family of bisphosphonate molecules developed for the treatment of osteolytic bone diseases. It shows high affinity for calcium and - as a consequence - adheres to bone if administered to vertebrates such as men. Osteoclasts play a role in the physiology of bone by breaking it down, opposed to osteoblasts who are involved in its reconstruction. It appeared that the activity of osteoclasts could be inhibited by bisphosphonate molecules sticked to bone.
Given that both osteoclasts and macrophages belong to the mononuclear phagocyte system (MPS), we decided to try clodronate as one of the first effector molecules in our planned "liposome mediated
macrophage suicide" approach.
Freely solved clodronate will not easily cross phospholipid bilayers such as liposome membranes and cell membranes. After injection, liposomes with encapsulated clodronate - used as Trojan horses - will be ingested and digested by macrophages. The encapsulated clodronate molecules are released within the cells and will accumulate there, since they are not able to leave the cell again. At a certain intracellular concentration, the clodronate molecules will induce apoptosis of the macrophage.
A lot of functional activities of macrophages have been discovered with the help of this approach since these activities were no longer performed or at least strongly reduced in macrophage-depleted animals.

The next step will be to produce a high-tech macro vacuum cleaner to make our own lives more pleasant!

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