ORGANISM REACTIVITY. ROLE OF REACTIVITY IN HUMAN PATHOLOGY

ORGANISM REACTIVITY. ROLE OF REACTIVITY IN HUMAN PATHOLOGY

 

PLAN

1.     Reactivity and resistance

2.     Types of reactivity

3.     Protective mechanisms; barriers (external,internal, SMPh)

4.     Cellular and humoral mechanisms of the reactivity. Role of the CNS and endocrine system in reactivity

5.     Role of constitution in pathology

 

Reactivity and resistance

Reactivity is ability of the organism to alter functional activity of the systems and organs for the adaptation of organism to new conditions of the environment for the survival. The concept “reactivity” is connected with the   concept “resistance”.

Resistance is a state of insusceptibility of an organism to the influence of pathogenic factors. There are such types of resistance: active and passive, primary and secondary, specific and unspecific. Active resistance is a result of the organism adaptation to the long time pathological factor influences. Passive resistance is a result of anatomical and physiological peculiarities of each organism. Primary (congenital) resistance is a result of the inherited peculiarities of an organism and it manifest itself after birth of the person. Secondary (acquired)  resistance is a result of organism functional reactions changes, which occur during the whole life. Unspecific resistance is the opposition  to the influence of many pathological agents. Specific resistance is the opposition to the defined agent influence, for example, microorganisms; its result is activation of the immune system.

 

 Types of reactivity

There are biological reactivity and individual reactivity.

Biological reactivity is a result of the morphological and physiological peculiarities of all individuals, which are of the same biological species. For example: some species of birds, fishes, and animal change the vital activity according to the changes of the seasons. The lowering of temperature of air promotes seasonal migration of birds to the places with higher temperature of air. During the period of reproduction many species of fishes move to the defined places for reproduction. Some animals can fall into a state of anabiosis, which is accompanied by lowering of their vital activity.

Individual reactivity is the reactivity of every individual. Individual reactivity is determined by age, sex, heredity, constitution, and functional conditions of organism’s regulatory systems, external environmental influences. For example: some diseases arise only in infant organism (measles, roseola, small pox, rachitis, scarlet-fever) but not in adult’s one. Children are less adapted to sharp changes of air temperature, but infant organism is more resistant to the hypoxia (oxygen deficiency), than adults. Resistance of the old organism to the infection reduces, but the number of cancer-ill adults and atherosclerotic-ill increases. Old people have very slowly developing inflammatory reaction. The dependence of the reactivity on sex can be explained by the morphological and physiological peculiarities of men and women. Reactivity of a female organism varies during the menstrual cycle time, pregnancy, climax. Resistance of a women to the hypoxia, hunger, and bleeding is better, than men’s. Women live longer, than men. But men are physically stronger.

 Individual reactivity of an organism is realized by specific and unspecific mechanisms.

  The specific mechanisms are formed by immune system. There are physiological specific mechanisms and pathological ones. The specific physiological mechanisms of the individual reactivity are the immune reactions, which form the specific resistance to some antigens (bacteries, viruses, fungus, tumours cells). The pathological specific mechanisms of the individual reactivity can cause development of the immunodeficiency or immunodepressive conditions of an organism or the allergic reactions and diseases.

The unspecific mechanisms of the reactivity are physiological and pathological. Physiological unspecific reactivity is the vital reactions complex of the healthy organism iormal life conditions. Pathological unspecific reactivity is the complex of an organism’s reactions in abnormal life conditions as a result of the decrease of the adaptive potential of an organism (for example: shock, collapse, narcosis).

Mechanisms of the unspecific reactivity are realized by means of nervous system reactions (central nervous system, vegetative nervous system), endocrine system reactions; barrier systems; cell’s reactions; humoral reactions.

The nervous and endocrine system are the main systems, which form the organism’s reactions on the various factors. The nervous system changes activity of receptors, neurons, nervous fibres, spinal cord and brain in the new vital conditions. The alteration of the nervous system activity changes the organism resistance. For example, the extreme stimulation of the central nervous system by coffeine reduces the resistance of an organism to hypoxia. The psychic trauma complicates the disease course. Reactivity of an organism depends on the vegetative nervous system conditions. Changes of  adrenergic  and  cholinergic link of the vegetative nervous system activity, which always is counterbalanced iormal conditions, characterize the organism’s adaptation to some influences of environment. The stimulation of the sympathoadrenal system on the first stages of adaptation is a protective reaction. In pathological conditions (for example, continuous hypoxia) the cholinergic link of the vegetative nervous system activation increases of an organism resistance to hypoxia.

Endocrine system takes the certain part in forming of the individual reactive mechanisms, so its alteration can complicate life of the human. The suprarenal gland function lessening reduces the resistance to hypoxia, hypofunction of the thyroid gland increases the resistance of an organism to hypoxia too, and the decrease of insulin excretion by pancreas elongates maim incarnation. The role of endocrine system and nervous systems, that operate synergically, is possible to explain on the example of stress-reaction. Canadian pathologist Selye was the first who has worked out the concept about stress. Stress is the unspecific reaction of an organism to different influences. Hypothalamus-hypophisis-suprarenal system plays the main role. This system carries out a general adaptive syndrome.

The barrier systems preserve an organism against the pathological factors of the external environment. There are external and internal barriers.

 

The external barriers

The external barriers are skin, mucous membranes, liver, spleen, lymphatic nodes and other organs, which have the cells of the system  of mononuclear phagocytes. The skin is covered with multilayer epithelium. It is a barrier for the majority of microorganisms.  Peeling of a surface layer promotes the deleting of bacteria. The clean skin has bactericidal activity, which depends on the рН of the sweat, on the structure of a secret of grease glands, on the excretion of antiseptic products. The mucous membranes, which cover conjunctiva, throat, respiratory, digestive and urogeninal tracts, prevent the penetration of microorganisms, due to the insignificant permeability. The secret of themucous coat glands and active function of glimmer epithelium promotes the mechanical deleting of dust, microorganisms. The bactericidal substance lysocim, which destroys some microorganism’s species, and the immunoglobulines are in the mucous coats secret. Protective reflexes, such as cough, sternutation, and delay of breath have the large value too. The gastric juice has bactericidal activity too, for example, kills of the cholera vibrion. Vomiting reflex also has protective function.

Many organs have barrier activity due to special cells, which form the system of mononuclear phagocytes (SМP). SMP is the system of cells, which are united due to 3 features: I) mutual function (all these cells are capable to phagocytes); 2) mutual derivation (all these cells derive from the stem cell of red bone marrow); 3) mutual structure (all these cells have one nucleus). All cells of the SМP occur from the stem cell of red bone marrow and develop according to such scheme: stem cell → promonocyte → monocyte. Monocytes enter into the blood and are divided into two groups: circulating and pre-wall. The pre-wall monocytes penetrate through the vessel wall and enter the tissues. Monocytes differentiation occurs in tissue and these cells transform into the macrophages of this organ. Tissue macrophages were found in various organs (table).

 

 The functions of cells of SМP are deleting of various particles from blood, lymph and tissues, due to absorption and enzymatic destruction of alien agent. Highly specific phagocytosis is the result of the specific structure of cellular membrane of macrophage: receptors to the immunoglobuline G, complement fractions and lymphokines (due tomacrophage and lymphocyte interaction) are placed on the membrane of macrophage and metabolic processes of the SМP cells are very active. The pathology of SМP cells can be hereditary and can occur during life. The hereditary defects of the enzymes myeloperoxidase, glucose-6-phosphatdehydrogenase, enzymes of glutation system, lysosomal hydrolases provoke the violation of macrophages protective functions. Primary metabolism violations of an organism (diabetes mellitus, obesity, atherosclerosis, uremia), malignant tumours, intoxication can cause the defects of macrophages too.

Internal barriers

There are internal barriers in the organism, which are named histohematic barriers. Wall of a capillary has the function of a barrier. The wall of a capillary lets in only the nutritious substances and does not let in the toxins, medicines. Examples of internal barriers: hematoencephalic (blood-brain), hematoophtalmic  (blood-eye tissue), hematolabirintic (blood-lymph of a labyrinth), hematoovarial (blood-ovarium tissue), hematotestical (blood-testicular tissue), placenta (mother’s blood-foetus blood). Connective tissue, which surrounds the vessels and penetrates into a tissue, executes the protective function too. The most powerful and complex barrier surrounds the nervous system and organs of reproduction. The nervous cells are the most sensitive to the internal environment changes. The hematoencephalic barrier permeability is various in different sites of the central nervous system. For example, hematoencephalic barrier in the area of hypothalamus lets pass all substances, which are in the blood. The information about the chemical structure of blood is necessary for the hypothalamus functions correction. The delay of the information can be dangerous for life. Hematoencephalic barrier includes the endotelium of the brain capillaries, their basal membrane, the glia and the brain coats. Hematoencephalic barrier structure: slots between endothelial cells of the capillaries are absent; glial cells cover all surface of the capillary; basal membrane is very dense. The peculiarity of the hematoencephalic barrier structure promotes protection of the brain against the influence of toxic substances. But in some cases this property complicates the treatment of some diseases of the nervous system. The permeability of barrier amplifies when the temperature of body increases. Doctors use this property for the treatment of infectious diseases of the nervous system. The protective function of barriers is dependend oervous and humoral influences, on a state of the external and internal environment. The alcohol has specific influence up hematoencephalic barrier. The permeability of this barrier increases during initial stage of alcoholism, so various toxic substances influence up the brain. Then permeability of the barrier decreases, that provokes violation of nutrition of the brain. Alcoholic psychoses, degradation of the person, premature aging develop in such patients. The alcohol easily damages reproductive system, poisons a foetus.

Cellular mechanisms

Cellular mechanisms of reactivity are manifested by the change of a functional state of a separate cell. The main effect of various cells reactions is adaptation to the conditions of the life, which permanently change. There are 2 types of adaptive cells reactions: immediate and continuous. The immediate mechanisms of cellular adaptation arise at once after the influence of stimulator and are realized due to present mechanisms. The continuous mechanisms of cellular adaptation arise gradually after durablis or multiplis influences of stimulator. The durablis influence of any factor promotes accumulation of the defined information in a cell and inclusion of mechanisms of self regulation. In a cell there is an interrelation of their function with the genetic apparatus. The increasing of influence functional load of cell strengthens activity of the genetic apparatus and promotes accumulation of some proteins, which must promote increasing of the function. The example of durablis adaptation is hypertrophy of a body, hyperplasia of a body.

Humoral mechanisms

Humoral mechanisms of the reactivity are very important for the organism too. The system of the plasma blood proteins, which is named system of complement, has the protective function. The system of complement and system of phagocytes have functional connection with immune system. Humoral factors are start mechanisms of the reactivity due to their operation on organs-effectors. The strongest substances are mediators and hormones. For example, the stress-reaction occurs due to the amplified excretion of norepinephrine (mediator), epinephrine (neurohormone), adrenotropic (hormon), glucocorticoids (hormones) and other substances. Individual reactivity can be changed as a result of influence of the factors of the external environment. Reactivity of an organism depends on ecology. Some changes of an ecological situation can prevent development of disease; others on the contrary provoke development of disease. For example: the small doze of a ultra-violet irradiation increases resistance of an organism to the infectious diseases, promotes synthesis of vitamin D in the organism, and the large doze promotes development of skin burn. The durablis operation of ionizing rays lowers resistance of an organism to infection. The intensive physical load is accompanied by significant psychoemotional overload and can provoke development of cardiovascular pathologies. The nonrational nutrition, hypovitaminosis lower resistance of an organism to an infection, promotes development of various violations of metabolism. Reactivity of the person can be changed as the result of the influence of alcohol, nicotine, automobile gases, which contain CO, Hg, Pb, industrial wastes. Sharp changes of weather, season of year and climate influence on reactivity and resistance too. Low temperature of air influences on organism variously. The overcooling lowers resistance to the infection, so in such conditions influenza and pneumonia may occur. The short-term contact of a human body with the cold environment, which periodically repeats, increases resistance of an organism to the infection. Low temperature (hypothermia) is used in medicine during complex continual operations on the heart and brain.

Progeria, Hutchinson-Gilford Progeria Syndrome, or Progeria syndrome) is an extremely rare genetic disease wherein symptoms resembling aspects of aging are manifested at a very early age. The word progeria comes from the Greek words “pro” (πρό), meaning “before” or “premature”, and “gēras” (γῆρας), meaning “old age”. The disorder has a very low incident rate, occurring in an estimated 1 per 8  million live births. Those born with progeria typically live to their mid teens and early twenties. It is a genetic condition that occurs as a new mutation, and is rarely inherited. Although the term progeria applies strictly speaking to all diseases characterized by premature aging symptoms, and is often used as such, it is often applied specifically in reference to Hutchinson-Gilford Progeria Syndrome (HGPS).

Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging. Progeria was first described in 1886 by  Jonathan Hutchinson. It was also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson-Gilford Progeria Syndrome (HGPS).

Children with progeria usually develop the first symptoms during their first few months. The earliest symptoms may include a failure to thrive and a localized scleroderma-like skin condition. As a child ages past infancy, additional conditions become apparent usually around 18-24 months. Limited growth, full-body alopecia, and a distinctive appearance (a small face with a shallow recessed jaw, and a pinched nose) are all characteristics of progeria. Signs and symptoms of this progressive disease tend to get worse as the child ages. Later, the condition causes wrinkled skin, atherosclerosis, kidney failure, loss of eyesight, hair loss, and cardiovascular problems. Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is prevalent. People diagnosed with this disorder usually have small, fragile bodies, like those of elderly people. The face is usually wrinkled, with a larger head in relation to the body, a narrow face and a beak nose. Prominent scalp veins are noticeable (made more obvious by alopecia), as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle, stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly population. Individuals do usually retain normal mental and motor development.

Iormal conditions, the LMNA gene codes for a structural protein called prelamin A. There is a farnesyl functional group attached to the carboxyl-terminus of its structure. The farnesyl group allows prelamin A to attach temporarily to the nuclear rim. Once the protein is attached, the farnesyl group is removed. Failure to remove this farnesyl group, permanently affixes the protein to the nuclear rim. Without its farnesyl group, prelamin A is referred to as lamin A. Lamin A, along with lamin B and lamin C, make up the nuclear lamina, which provides structural support to the nucleus.

Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered to be a point mutation in position 1824 of the LMNA gene, in which cytosine is replaced with thymine. This mutation causes transcription of the LMNA gene to stop too early, which results in the creation of an abnormally short mRNA transcript. This mRNA strand, when translated, yields an abnormal variant of the prelamin A protein whose farnesyl group cannot be removed. Because its farnesyl group cannot be removed, this abnormal protein, referred to as progerin, is permanently affixed to the nuclear rim, and therefore does not become part of the nuclear lamina. Without lamin A, the nuclear lamina is unable to provide the nuclear envelope with adequate structural support, causing it to take on an abnormal shape. Since the support that the nuclear lamina normally provides is necessary for the organizing of chromatin during mitosis, weakening of the nuclear lamina limits the ability of the cell to divide.

Progerin may also play a role iormal human aging, since its production is activated in senescent wildtype cells.

Unlike “accelerated aging diseases” (such as Werner’s syndrome, Cockayne’s syndrome, or xeroderma pigmentosum), progeria is not caused by defective DNA repair. Because these diseases cause changes in different aspects of aging, but never in every aspect, they are often called “segmental progerias“.

Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. A genetic test for LMNA mutations can confirm the diagnosis of progeria.

No treatments have been proven effective. Most treatment focuses on reducing complications (such as cardiovascular disease) with heart bypass surgery or low-dose aspirin. Children may also benefit from a high-energy diet.

Growth hormone treatment has been attempted. The use of  morpholinos  has also been attempted in order to reduce progerin production. Antisense Morpholino oligonucleotides specifically directed against the mutated exon 11-exon 12 junction in the mutated pre-mRNAs were used.

A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited toanimal models

. A Phase II clinical trial using the FTI  lonafarnib began in May 2007.  In studies on the cells another anti-cancer drug, rapamycin, caused removal of progerin from the nuclear membrane through autophagy. It has been proved that pravastatin and zoledronate are effective drugs when it comes to the blocking of farnesyl group production. However, it is important to remember that no treatment is able to cure progeria.

Farnesyltransferase inhibitors (FTIs) are drugs which inhibit the activity of an enzyme needed in order to make a link between progerin proteins and farnesyl groups. This link generates the permanent attachment of the progerin to the nuclear rim. In progeria, cellular damage can be appreciated because that attachment takes place and the nucleus is not in a normal state. Lonafarnib is an FTI, which means it can avoid this link, so progerin caot remain attached to the nucleus rim and it now has a more normal state. The delivery of Lonafarnib is not approved by the US Food and Drug Administration (FDA). Therefore, it can only be used in certain clinical trials. Until the treatment of FTIs is implemented in progeria children we will not know its effects—which are positive in mice.

Pravastatin, traded as Pravachol or Selektine, is included in the family of statins. As well as zoledronate (also known as Zometa and Reclast, which is a bisphosphonate), its utility in Hutchinson-Gilford progeria syndrome (HGPS) is the prevention of farnesyl groups formation, which progerin needs to provoke the disease. Some animal trials have been realized using FTIs or a combination of pravastatin and zoledronate so as to observe whether they are capable of reversing abnormal nuclei. The results, obtained by blinded electron microscopic analysis and immunofluorescence microscopy, showed that nucleus abnormalities could be reversed in transgenic mice expressing progerin. The reversion was also observed in vivo – cultured cells from human subjects with progeria – due to the action of the pharmacs, which block protein prenylation (transfer of a farnesyl polypeptide to C-terminal cysteine). The authors of that trial add, when it comes to the results, that: “They further suggest that skin biopsy may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects with HGPS in clinical trials”. Unlike FTIs, pravastatin and zoledronate were approved by the U.S. FDA (in 2006 and 2001 respectively), although they are not sold as a treatment for progeria. Pravastatin is used to decrease cholesterol levels and zoledronate to preventhypercalcaemia

.

Rapamycin, also known as Sirolimus, is a macrolide. There are recent studies concerning rapamycin which conclude that it can minimize the phenotypic effects of progeria fibroblasts. Other observed consequences of its use are: abolishment of nuclear blebbing, degradation of progerin in affected cells and reduction of insoluble progerin aggregates formation. All these results do not come from any clinical trial, although it is believed that the treatment might benefit HGPS kids.^[13]

A 2012 study showed that the cancer drug  Lonafarnib can be used to treat progeria.

It should always be taken in account that no treatment is delivered in order to cure Hutchinson-Gilford progeria syndrome; all potential drugs are in pre-clinical stages.

As there is no known cure, few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.

Mental development is not adversely affected; in fact, intelligence tends to be above average. With respect to the features of aging that progeria appears to manifest, the development of symptoms is comparable to aging at a rate eight to ten times faster thaormal. With respect to features of aging that progeria does not exhibit, patients show noneurodegeneration or cancer predisposition. They also do not develop the so-called “wear and tear” conditions commonly associated with aging, such as cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).

Although there may not be any successful treatments for progeria itself, there are treatments for the problems it causes, such as arthritic, respiratory, and cardiovascular problems.

A study from the Netherlands has shown an incidence of 1 in 4 million births (within the Netherlands).  Currently, there are 80 known cases in the world. Approximately 140 cases have been reported in medical history.

Classical Hutchinson-Gilford Progeria Syndrome is usually caused by a sporadic mutation taking place during the early stages of embryo development. It is almost never passed on from affected parent to child, as affected children rarely live long enough to have children themselves.

There have been only two cases in which a healthy person was known to carry the LMNA mutation that causes progeria. These carriers were identified because they passed it on to their children. One family from India has five children with progeria, though not the classical HGPS type. This family was the subject of a 2005 Bodyshock documentary entitled The 80 Year Old Children. Another family from Belgium has two children with progeria.

The first reported case of a black African child with progeria was identified in September, 2011. The South African child, named Ontlametse Phalatse, was born in 1999. The Progeria Research Foundation  at  Children’s Hospital Boston, affiliated with the Harvard University Medical School, is treating her and monitoring her case.

Role of constitution in pathology

Constitution is a complex of functional and morphological peculiarities of an organism, which were derivated by the heredity, and which forms during all life as a result of influences of the environmental factors, it determines reactivity of every individual. All people belong to some constitutional type. Hyppocrate (firstly) had determined some types of the constitution and had divided all people on four types: choleric, sanguinic, phlegmatic and melancholic. The physicians, who lived `in Hyppocrates times, knew, that the individual peculiarities of the person determined his reaction on the external environment and caused disease course peculiarities.

Sigo had divided all people into 4 morphological types. This classification is based on the peculiarities of the anatomic structure of the person. Constitution types by Sigo are: respiratory type, digestive type,muscular type, and brain type.

M.V.Chornoruzkiy has offered the classification, based on the functional peculiarities of an organism. Constitution types by Chornoruzkiy are: normosthenic,  hypersthenic,  asthenic.

А.А.Bogomoletz  has offered the classification, which characterizes  the connective tissue peculiarities. Constitution types by Bogomoletzare: asthenic type, fibrosis type, pastosis type, and lipomatosis  type.  Constitutional  type of an organism plays important role in the development of the pathological process.

Diathesis

Diathesis is the manifestation of the abnormal constitution. Diathesis is characterized by abnormal reaction of an organism to the physiological and pathological influences.Diathesis appears the most frequently during the childhood, because the homeostatic regulation mechanisms are imperfect. There are 4 types of the diathesis: exudative-cataral, lymphohypoplastic, nervous-arthritic, asthenic. Very intensive exudative processes, allergy reactions and long disease course characterize the development of the inflammation in such patients, who are suffering from the exudative-cataral diathesis. Allergic reactions are the result of the high level of immunoglobulines in the patient’s blood, so bronchial asthma, and anaphylactic shock саn develop very often. The patients, who are suffering from the lymphohypoplastic diathesis, are usually pale, theirs musculartissue is developed deficiently, the lymphatic nodes size is increased. The aytoallergic diseases arise in these patients very often. Nervous-arthritic diathesis cause the obesity intensification, nervous system irritability, diseases of joints, skin diseases, psychological disorders in some patients. Astenic diathesis is characterized by adynamia; lability of vascular reactions and gastroptosis. Diathesis is not a fatal condition of the patient. The environment can promote or inhibit its manifestation. The causes of many forms of diathesis, probably, are hereditary pathology of different enzymes.

Stress requires specific reactions in order to carry out immediate and effective measures for the necessary adaptation of the entire organism. Eduardo Arzt, University of Buenos Aires, Argentina, and Florian Holsboer, Max-Planck Institute of Psychiatry, Munich, have managed to detect how stress governs these regulatory processes on the cellular level. They identified a factor (RSUME, RWD-containing sumoylation enhancer) that enhances the alteration of proteins by small ubiquitin-like molecules (sumoylation). This alteration stabilizes, activates, or modifies the function of the proteins concerned and is the basis of a successful stress reaction. RSUME was detected in tumor cells that are in general stressed due to chronic lack of oxygen (hypoxia). The elucidation of the regulatory circuits governed by RSUME could allow for future therapeutic interventions in tumor therapy, perinatal hypoxia, stroke and brain trauma. (Cell 131, 309-323, 2007)

 External factors like e.g. cold, heat, poison or lack of oxygen, or internal factors like emotional imbalance destabilize an organism. A fine-tuned system of molecular, cellular, hormonal, and neuronal reactions immediately tries to re-establish the previous balance of the organism.

 In recent years molecular genetic studies have allowed for new insights into the underlying regulatory processes. In order to warrant a fast reactivity of the organism to outer and inner alterations, existing proteins are altered by binding to so-called SUMO molecules (sumoylation), which affects their stability, activity and functionality, thus aiming at rebalancing. So far, however, it had only partly been elucidated how the process of sumoylation is triggered, e.g. in a stressful situation.

In a publication in the scientific journal “Cell” the scientists describe the identification of RSUME that is activated in cellular stress like hypoxia or heat shock and hence elicits an intense sumoylation reaction. In doing so it reinforces the binding of the involved reactants and affects the selection of the proteins to be altered. Thus RSUME is significantly involved in the specificity of the triggered alterations and couples stress and sumoylation on the molecular level. The authors could show that RSUME causes the specific sumoylation of IκB and hence the activation of regulatory genetic factors like NF-κB and HIF-1α as central switches in vascular and tumor genesis.