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Ozone Therapy 2016; volume 1:6270
[Ozone Therapy 2016; 1:6270] [page 25]
Abstract
The panniculosis or panniculopathy edematous fibro sclerotic
(PEFS), commonly called cellulite is a subcutaneous adipose disease
that afflicts the vast majority of women at all ages. PEFS is framed as a
subcutaneous adipose suffering from venous and lymphatic stasis
whose etiology is multifactorial. Many others are the implications and
clinical relapses of diseases of inflammatory or autoimmune basis that
determine disease states with involvement of the patient’s general con-
ditions. The oxygen-ozone therapy, thanks to its abilities of improving
the rheological properties of the microcirculation, immuno-modulating
and anti-inflammatory abnormalities, arises as adjuvant and is a valid
method, which is also alternative compared to conventional protocols.
Introduction
With this work I want to expose and support the thesis that the oxy-
gen-ozone (O2-O3)therapy is a broad therapeutic application in diseases
of the adipose tissue of local and systemic interest, tracing an exhibition
on the possible applications in various pathological conditions.
Inflammatory or degenerative events affecting the subcutaneous
tissue are characterized by alterations of the fat cells, stromal and vas-
cular system.1They can lead to hypertrophy, atrophy, disintegration
and necrosis of the adipose tissue.2Examples of lipodystrophy are the
Barraquer-Simon disease, a nodular fever characterized by inflamma-
tory nodules under the skin with matching surface of erythema,3the
adiponecrosis that can be caused by crushing, freezing, injections of
lipolytic drugs, continuous mechanical injuries such as those caused
by a violent percussive massage or skin application of machinery,
whose symptomatology is characterized by inflammation pain, erythe-
ma, hemorrhage, and finally tissue necrosis.3,4 This brief exposure
includes panniculosis or panniculopathy edematous fibro sclerotic
(PEFS) commonly called cellulite.
Today, O2-O3therapy is recognized by many as an excellent and
effective medical method for the treatment of several diseases. Several
countries around the world practice it in their own hospitals, clinics
and universities, acting on various diseases.
For a long time fat has been considered little involved in the
processes that regulate the body, relegating it to purely thermal and
mechanical barrier function as well as to that of storage and energy
storage in the form of triglycerides, and then returning it as free fatty
acids according to the body’s needs.1
Today, in the light of current research and results, it is considered a
real vocation in endocrine tissue, involved in many metabolic mecha-
nisms by which it exercises fundamental roles for the production and
synthesis of complex signals involved in the conversation between
even distant organs.2In obesity, the amount of impaired secretion of
adipokines determines important circulatory and metabolic disorders,
acting as a co-factor in pagenesi of cardiovascular disease and meta-
bolic syndrome.1,2
Oxygen-ozone therapy
The treatment with O2-O3uses a gas mixture with different concen-
trations of O3, establishing itself as an effective and versatile tech-
nique available to the clinicians.
Ozone is an allotropic form of oxygen in the atmosphere that
absorbs most of the ultraviolet radiation emanating from the sun,
allowing on the surface life.
The O2-O3therapy is a macroterapia that reactivates microcircula-
tion.5It works by improving the oxygenation in different tissues, and
exerts a protective multi-organ action.
The therapeutic effects of O2-O3mixtures are due to a controlled
oxidative stress,6which triggers as in a paradox many metabolic factors,
in relation to the pathological picture and the predicted clinical outcome.
The O2-O3possesses powerful anti-edema and anti-inflammatory
activity being widely endeavored in diseases characterized by inflamma-
tion affecting the arterial circulatory system, venous and lymphatic.5,6
Ozone possesses anti-inflammatory action due to the reduction of the
production of prostaglandins by acting on the synthesis of arachidonic
acid and also has an antioxidant action for activation of the protective
enzymatic functions of endogenous cells against free radicals.7,8
The use of O2-O3in youth is benign. Hypodermatitis causes an
Correspondence: Gaetano Cuccio, Doctor II Master Oxygen-Ozone
University of Pavia, Oxygen-Ozone Therapy Scientific Society, Via Roma 69,
24020 Gorle (BG), Italy.
Tel: +39.091.664645. E-mail: gaetanocuccio28@libero.it
Key words: PEFS; Cellulite; Oxygen-ozone; Adipose; Microcirculation.
Conflict of interest: the authors declare no potential conflict of interest.
Received for publication: 21 June 2016.
Accepted for publication: 25 July 2016.
©Copyright G. Cuccio and M. Franzini, 2016
Licensee PAGEPress, Italy
Ozone Therapy 2016; 6270
doi:10.4081/ozone.2016.6270
This article is distributed under the terms of the Creative Commons
Attribution Noncommercial License (by-nc 4.0) which permits any noncom-
mercial use, distribution, and reproduction in any medium, provided the orig-
inal author(s) and source are credited.
Oxygen-ozone therapy in the treatment of tissue adipose diseases
Gaetano Cuccio,1Marianno Franzini2
1Doctor II Master Oxygen-Ozone University of Pavia, Pavia; 2Oxygen-Ozone Therapy Scientific
Society, Gorle (BG), Italy
Non-commercial use only
immediate benefit, with an obvious reduction of edema due to
increased lymphatic drainage activities and improved perfusion of the
vessels. The reduced capacity in the functioning of the microcircula-
tion causes, with the relative slowdown of the blood and lymphatic cir-
culation, an excessive accumulation of cellular catabolites in the tis-
sues, creating a sort of self-intoxication and greater permanence of
free radicals, with consequent damage of the cell structures and tissue
aging.8
The experience together with continuous research have identified
for the therapeutic window8,9 optimal concentrations of O2-O3,
processed with the efficacy and safety criteria as those reported by the
protocols provided by the Società Scientifica di Ossigeno Ozono Terapia.
The therapy with O2-O3is considered as an absolute medical method
with less risk and fewer side effects for the patient.
Mechanisms of action
Ozone is an unstable molecule that, dissolved in aqueous solution,
reacts instantly with substrates such as unsaturated fatty acids,5,9 with
reducing compounds such as reduced glutathione and some water sol-
uble proteins such as uric acid, ascorbic acid, albumin, glucose, and
those cysteine-rich.6,8
The biochemical reactions determinate the formation of an excess of
H2O2that spreading in cells activates many metabolic pathways. At the
same time the excess of H2O2is reduced by the intracellular antioxi-
dant system.8,9 Our thesis is inspired by the observations of the effects,
which produces O2-O3therapy in patients with disorders of the fat tis-
sue with different etiology.
The O2-O3therapy applications in the treatment of antiviral infec-
tions collect successes due to the ability of the ozone to modulate, in
the acute phase, the synthesis of immunoglobulins, particularly IgM,
through the activation of immunocompetent cells of the anti-infection
defenses complementary to those specifications.5,7,8
The mechanism of action of O2-O3about viruses can be attributed to
oxidative capacity and the consequent inactivation of specific viral
receptors used to create the bond with the wall of the cell to infect. In
other words, while in bacteria the O3acts with destructive action, in the
virus it is inhibited by the adhesion mechanisms of cell reproduction
before the attack.5
Mechanisms of action on inflammation
of oxygen-ozone
Histopathological events dictated by immune and hemodynamic con-
ditions suggest a broad use of therapy with O2-O3.
The immunomodulatory properties, anti-inflammatory, antiviral,
antibacterial, and the ability to improve perfusion of the microcircula-
tion and thus restore a proper metabolic conversation between the ves-
sel system, the functions and the neighborhood, make this method
probably elective to afford clinical conditions involving the adipose tis-
sue as a forum for primary lesions, as predisposing factor in the patho-
genesis of some metabolic diseases, or as a target in metabolic dramat-
ic events as the steatonecrosis pancreatic or acute hemorrhagic pan-
creatitis.9,10
As it is known, the O2-O3is used for the intense immunomodulatory
action. In fact, it was demonstrated that blood samples incubated with
O2-O3mixtures showed increased production of interferon-y (IFN-g) and
transforming growth factor β1 (TGF-β1).9The increase in non-specific
immune defenses has been characterized by the increased presence of
INF-gso, as it has been found, is the release of IFN-βand other
cytokines such as interleukin (IL) 2,6,8, tumor necrosis factor (TNF-α),
TGF-βand a granulopoietina (GM-CSF).5,7-9
Another fundamental property of O3is realized on the metabolism of
carbohydrates, proteins and on fatty acids. The aerobic demolition of
glucose in therapy O2-O3, increases the availability of adenosine
triphosphate (ATP) that is most required in degenerative and inflam-
matory diseases, and intervenes in the metabolism of protein for its
affinity for sulfhydryl groups, reacting with essential amino acids such
as methionine and tryptophan or cysteine that contain sulfur.5,7,8 In the
unsaturated fatty acid it is linked to the double carbon bond, trans-
formed into water-soluble compounds.5
O3favors the formation of peroxides exerting antibacterial effect with
a mechanism similar to that used by white blood cells used to bacterial
phagocytosis. With viruses it has a virustatic action by preventing their
adherence to the cellular receptors.5The formation of peroxides inter-
venes on erythrocyte metabolism. The O3develops an interaction with
the double bonds of unsaturated fatty acids of the layer of the phospho-
lipids in the erythrocyte membrane by increasing the deformability,
thereby reducing blood viscosity, increases the production of 2.3-diphos-
phoglycerate, responsible of the O2supply of the hemoglobin to tissues,
with better perfusion and transport along the vascular beds.5,8,11
O3has an anti-inflammatory action by reducing the production of
proinflammatory cytokines IL-2, IL-4, IFN-gTNF-α, Th2 activation and
suppression of Th1, the ratio CD4+/CD8+(P<0.05) with CD3+ human
leukocyte antigens-idiosyncratic drug reactions constant value in the
multiple sclerosis,12 immunoglobulins and inflammatory mediators as
well as circulating immune complexes, antioxidant enzymes such as
catalase, the superoxide dismutase, glutathione, it also reduces C-reac-
tive protein, total cholesterol, low-density lipoprotein and triglycerides
and homocysteine and finally increases the high-density lipoprotein.5-8
The O2-O3acts on the cell-mediated inflammatory response7due to
improved tissue oxygenation and cellular districts, inhibiting: activa-
tion and leukocyte and platelet adhesion, activation of phospholipase
A2 that with its enzymatic action on food on arachidonic acid increases
the amount of prostaglandins and leukotrienes, the cyclooxygenase and
metalloprotease, by neutralizing endogenous reactive oxygen species
and stimulating local production of antioxidant enzymes.5,7,8
O3causes immediate analgesic effect in the inoculation site for inac-
tive and destroys algogenic substances, it inactivates bradykinin, alters
serotonin which has an indole nucleus, and produces a long-lasting
analgesic effect through the denaturation of some cellular proteins
such as kininogen and kallikrein, alteration of receptor sites for
algogenic substances and increased gene expression for the antinoci-
ceptive activity.7-9
Body fat
Adipose tissue is considered by many scholars as a true common
organ for its diverse endocrine and metabolic functions.1,2 Adipose tis-
sue is found primarily in the subcutaneous layer where it forms pan-
niculus of various thickness, consisting of aggregations of adipocytes
thickly pushed together and wrapped in a web of reticular fibers, divid-
ed into lobules by connective tissue septa, where there is a dense net-
work of vessels with each adipocyte is in contact.13 Since a few years it
has been shown that the fat is not only a warehouse responsible for the
conservation of the excess calories in the form of triglycerides or the
release of fatty acids according to the needs.1There is a direct relation-
ship between the increase in body fat and the production of fatty acids
(FFA), hormones, and proaterogene of proinflammatory molecules,
which together are involved on complications associated with obesity,
diabetes, hypertension and dyslipidemia, coming to the metabolic syn-
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drome.1,2 The greatest amount of proinflammatory molecules would
seem to be issued by the nonfat cells of the adipose tissue itself, such
as eosinophilic cells, monocytes and macrophages. With the exception
of leptin and adiponectin only secreted by adipocytes, the release of
interleukins and a number of inflammatory cytokines, such as the pro-
duction of growth factors and defense, are more chargeable to other
subcutaneous cellular components. The tissue suffering caused by pro-
inflammatory molecules determines a state of cellular hypoxia, with
consequent increase of angiogenesis, the greatest amount of connec-
tive tissue, the number of fibroblasts and macrophages.1,2
In overweight, the morphological and functional alterations of the
subcutaneous tissue do not affect only the adipocyte. Through neural
nutritional hormonal and paracrine mechanisms the increase of adipo-
genesis stimulates the recruitment and proliferation of mesenchymal
precursors - preadipocytes - and their subsequent differentiation into
mature forms Fat Cells.1,2
The inflammatory response leads to the alteration of the tissue com-
ponents, for the most part of those relevant to the extracellular matrix
exacerbated by endothelial fibrosis.14
Anatomical memories: the fatty tissue
Adipose tissue is 15-20% of total body weight. The amount is widely
variable in relation to age, gender, body site and nutritional status. Many
features, among which that of mechanical protection and thermal insula-
tion body, act also as a storage site and reserves of energy metabolites.
The ability of adipose tissue to accumulate triglycerides is virtually unlim-
ited, and adipocytes may undergo hypertrophy by accumulation in the
order of thousands of times. The adipose tissue intervenes in the mecha-
nisms of thermogenesis and in the maintenance of body temperature and
is capable of secreting nature of hormone or hormone-like substances.1
There are two types of adipose tissue the so-called white to yellowish
color due to the presence of pigmented substances such as carotenoids
and bile pigments and the brown, dark in color because of a large num-
ber of mitochondria, but little expressed in the adult and with exclu-
sively thermogenic functions.
White adipose tissue is distributed primarily in the subcutaneous
tissue around the kidney, mesentery, in the yellow bone marrow, in the
retroperitoneal regions, axillary and inguinal, between the fibers of
skeletal muscle or around the myocardium. It is almost non-existent on
the eyelids, the ear and the scrotum and reaches its maximum thick-
ness at the gluteal region.
When observed it is of yellowish color, due to the presence of pig-
mented substances such as carotenoids and bile pigments. It presents
a scaffold connective, coming from the dermis, in its turn connected to
the underlying muscle groups, organized in different thickness baffles
which delimit the lobules organized in globular clusters composed by
cells of mesenchymal origin, adipocytes or fat cells.
In the subcutaneous adipose tissue, we can distinguish a superficial
areolar layer and a deep lamellar layer. In the first level lobules tend to
assume a round shape, in the second they are flattened with the major
axis parallel to the body surface, separated from connective retinacula
and also oriented according to the cutaneous plane.15 The laminated
layer is a moving area, which allows the sliding of the skin at the mus-
culoskeletal level.
The amount of subcutaneous fat differs in relation to nutritional sta-
tus, age and gender. The regional distribution is a secondary sexual
character, determined by secreted steroid hormones and especially
from the gonads.
In the female, after puberty, there is an increase in subcutaneous fat
levels, mainly in the buttocks, hips, thighs and breasts. In the male, lipid
deposits are mostly distributed on the trunk and abdomen. Sex and its
endocrine framework also affect the organization of the adipose tissue,
resulting in histological differences.14 The dermal-hypodermic boundary
is, therefore, characterized by a hill profile that, even before the develop-
ment of cellulite (a typically female imperfection) can be highlighted by
putting in traction the connective inextensible branches (Figure 1).15
In the case of obesity, the lobules increase in volume but are held
back, along the edges, by the branches around them. Their apexes pro-
trude into the dermis, as dome-shaped pads (fat buds) creating the
hated blemish skin of so-called orange peel.15 The unsightly alternating
depressions and elevations are evident at first only during standing,
even in recumbency.
Conversely, in the male subcutaneous, the branches of the areolar
plan assume an oblique course, crossing to delimit smaller lobules, of
polygonal shape, which, even in the case of hyper-lipid accumulation,
does not tend to protrude toward the dermis.
The brown adipose tissue, which is found only in mammals, is pre-
dominantly localized in the subcutaneous interscapular region, axil-
lary, perivisceral outside the hypodermis, along the large blood vessel,
around the kidney and adrenal gland, appearing in the fresh prepara-
tions with a dark coloring due to the rich vasculature and the presence
of numerous cytochromes placed on mitochondria.
In women, the connective branches in the areolar layer have an
arrangement which is perpendicular to the cutaneous plane, separating
bulky lobules in rectangular section, whose quotes press against the
reticular dermis and will protrude in the form of fat buds of hemispheri-
cal shape.15
Production of adipokines in adipose tissue
In obese, as well as in localized accumulations of fat, the adipocyte
hypertrophy, therefore usually a higher energy intake, sets in motion at
cascade profologistic processes causing increased vascularization of
adipose tissue with macrophage infiltration, release of inflammatory
cytokines, insulin-local resistance, accelerated lipolysis with the
release of FFA, decreased production of adiponectin and increased pro-
duction of leptin.1,2 Today it is clear that the altered secretion of
adipokines in obesity, especially abdominal, as well as in localized fat,
determines important circulatory and metabolic disorders. In visceral
fat tissue and subcutaneous, especially in the obese, in particular
inflammation and edema of stasis conditions, we are seeing increased
[Ozone Therapy 2016; 1:6270] [page 27]
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Figure 1. Organization of subcutaneous adipose tissue in the
male (left) and female (right) gender. In humans, the branches
that delimit the lobules of the connective areolar layer assume an
oblique course, while in the woman are arranged in an orthogo-
nal manner to the cutaneous plane characterizing the classic hill
profile of the dermo-hypodermic border.
Non-commercial use only
production of interleukins proflogistiche (IL-6, IL-8), angiotensinogen,
plasminogen activator inhibitor-1, TNF-αand growth factors, species of
vascular endothelial growth. Many of these factors are produced by
stromo-vascular fraction of adipose tissue and macrophages infiltrat-
ing the adipose tissue.13
In addition to determining a proflogistic environment, the products
of visceral adipocytes, unlike those of the subcutaneous tissue, have
direct access to the liver, thus magnifying the negative consequences
due to the excess of visceral fat. Many of these have a role in the rela-
tionship between central obesity, cardiovascular disease, dyslipidemia,
type-two diabetes and systemic inflammation.
In diseases involving the subcutaneous adipose, it is reasonable to
think that in tissue pain conditions, with no pathological evidence, the
adipocytes can produce inflammation of factors, chemotactic factors
and proteins of the complement cascade.14
Diseases of the subcutaneous adipose tissue
These annoying, sometimes disabling, diseases are rarely fatal, but
mostly benign, therefore they have received little attention from main-
stream medicine.
For the particular anatomical location of the adipose tissue and patho-
physiological phenomena that involve local and systemic character, there
is no specific medical branch of belonging, in the sense that the condi-
tions which can affect the fat tissue may be attributable to the dermatol-
ogist, as well as the rheumatologist, as well as the internist and so on.
Vasculitis
The lesions of the microcirculatory units (MCUs) vessels are charac-
terized by inflammatory processes affecting the wall of the arteries,
veins and capillaries and other tissue components.13 The inflammatory
process leads in most cases to immune pathogenesis, it can be charac-
terized by the formation of immune complexes induced by heterologous
antigens, such as viruses, bacteria, parasites autologous antigens such
as Ig, DNA, neoplastic, of unknown nature, cell mediated hypersensitiv-
ity presenting necrotic infiltrative disorders, granulomatous manifesta-
tions and intermediate aspects.4,13,14 In MCUs, as well as in large ves-
sels, inflammation and degenerative processes can affect the arterial
side as venous or both involving the system of the capillary network.
In general, the drugs used for the therapy of vasculitis are corticos-
teroids and antibiotics and this suggests the application of therapy with
O2-O3for the well-known anti-inflammatory properties as well
immunomodulatory, anti-edema, static virus, bactericide, and for the
ability to re-oxygenate the tissue and make the streets of the microcir-
culation more pervious to the passage of blood.
Therapeutic actions ozone on microcirculation
As before mentioned, the microcirculation, the surface of which has
a development of about 6000 m2, consists of arterioles, capillaries and
arterioles destination, which respectively have diameters of 20-50, 10-
15 and 5-9 μ. The flow in the capillary is controlled by sphincters pre
capillaries where the blood, flowing, exchanges its nutritive factors, pro-
vides oxygen to the tissues and reabsorbs the products of cellular catab-
olism and carbon dioxide. The flow inside the capillary district is due to
the pressure gradient between the arterial end, whose pressure is 32
mmHg, and the venous end, which is of about 15 mmHg. The transit
time of the erythrocytes is about 1-2 seconds in the capillaries, the
length of which is about 0.10 to 0.15 mm. The flow r
ate is very low if
compared with that of the aorta and iliac where it is approximately 100
cm second. The red blood cell, which has a diameter of about 5-8 μ, has
normally a larger diameter of the capillary, to be able to cross it, deform-
ing and adapting itself to the diameter of the vessel. According to the
law of Poiselle the blood flow in a system of rigid pipes is directly pro-
portional to the pr
essure difference between the extremes of the consid-
ered pipe and directly proportional to the fourth power of the radius. A
small reduction of this determines the reduction of the flow, which
results to be inversely proportional to the length of the vessel and the
blood viscosity, that is, the resistance to flow and to the deformability of
red blood cells. Blood viscosity is affected by hematocrit,
the concentra-
tion of fibrinogen, by globulins suspended in plasma, and the deforma-
bility of red blood cells, as well as the aggregation of platelets and leuko-
cytes, which are larger and more deformable than red blood cells.
O3can be used in all forms of a disease in which there is a reduced
supply of oxygen because it has an effect of reactivation of the microcir-
culation and multi organ protective action: i) peripheral arteriopathy of
the lower limbs; ii) ischemic heart disease; iii) vascular renal impair-
ment; iv) cerebrovascular diseases; v) maculopatia degenerative retinal.
O3causes an increase in red cell deformability and filterability
because it breaks the long chains of fatty acids controlled by lipid per-
oxidation, increases the production of 3.2 diphosphoglycerate with
greater supply of oxygen to peripheral tissues by moving to the right of
the hemoglobin dissociation curve, reduces platelet aggregation and
plasma viscosity, reduces plasma fibrinogen, activates the energy
metabolism in the mitochondria with increased production of ATP; it
determines an increase of the blood flow, the release of nitric oxide at
the level of pre-capillary sphincters by endothelial cells, it has an anti-
nflammatory action resulting in a reduction in the production of
prostaglandins and acting on Food on arachidonic acid, moreoves, it
has an antioxidant action by activating protective antioxidant enzyme
functions of endogenous cells.5-8,11
Diseases of the subcutaneous adipose with
mainly inflammatory and degenerative features
These issues should deserve a much greater discussion, and in this
paper I would like, altough in a non-exhaustive way, to take into
account as main theme the panniculus injuries that sometimes charac-
terize the framework of a large family of diseases involving the adipose
tissue (Table 1).
Erythema nodosum
Erythema nodosum is a seasonal disease (spring, fall), common in
young women, characterized by the appearance of skin nodules mostly
in the legs (front part of the legs), and more rarely in the upper limbs
and buttocks.4
The disease, with cast successors can last 4-6 weeks and is preceded
by a general framework of symptoms characterized by fever, arthralgia,
gastrointestinal disorders, tonsillitis, etc. In the resolution period, the
general symptoms subside and skin lesions change their color to red-
dish or purplish red in blue, yellow-green and finally yellow (look
bruised forms) reabsorbing without traces.
Erythema nodosum is an affection of the deep dermis and subcuta-
neous tissue on the basis of vasculitis with important allergic compo-
nent4which recognizes multiple and varied causes.
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Skin lesions appear as multiple knots, four or more each limb, slight-
ly prominent on the skin plans of the diameter from 1 to 8 cm, with
sharp boundaries, painful on palpation, a hard consistency with red or
purplish red appearance that is thrown to externalize successively. The
cycle of each element is 10-20 days without results. Histologically, an
infiltrate consisting primarily of neutrophils in the dermal and subder-
mal connective limits and in subcutaneous septa can be noticed.14
Vessels in charge of the wall, are infiltrative phenomena and endothe-
lial proliferation. Characteristics of Miescher nodules affect the deep
dermis and the subcutaneous fibrous septa (Table 2).13
The symmetry of the lesions, the general symptoms, the characteris-
tic color change of the knots and especially the spontaneous resolution
without scars are characteristic of erythema nodosum.4
The differential diagnosis with other diseases such as nodular expres-
sion hardened erythema of Bazin, fungal tires, tuberculosis and leutiche,
or rheumatic fever, where, however, subcutaneous nodular lesions, which
are very rare in adults, are small, hard, not sore and not inflamed.14
The causes have to be excluded for the first streptococcal infection
(title ASLO streptozyme tests, throat swab) and sarcoidosis [RX chest,
angiotensin converting enzyme dosage serum, eye examination
(uveitis)].
In children before the age of five, most cases were secondary to
tuberculosis, while after ten the most common cause and streptococcal
infection was beta hemolytic group. Other causes have to be found in
inflammatory bowel disease and upper airway.
Classical therapy
Causal therapy: eliminate antigen or drug; symptomatic treatment:
[Ozone Therapy 2016; 1:6270] [page 29]
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Table1. Diseases of connective and subcutaneous adipose tissue.
Panniculitis or Hypodermatitis Christian-Weber panniculitis (rare)
Hypodermitis stasis (common)
Erythema nodosum (common)
Bazin hardened erythema (rare)
Lipomatosis Solitary lipomas (common)
Symmetrical lipomas in lipodystrophy cerebrospinal chest:
- supraclavicular
- trochanteric
- intra periarticular of knees, legs and ankles, (all common)
Madelung disease (rare)
Dercum syndrome (painful lipomatosis, rare)
Universal diffuse lipomatosis (rare)
Hoffman-Zurhelle syndrome (rare)
Teutschlander syndrome or calcinosis lipogranulomatosis progressive justa-articular (elbows, rare), also it affects late teens
Panniculosis Women cellulitis or PEFS alteration of subcutaneal fat (very common)
Table 2. Etiological factors of erythema nodosum.
Bacterial infections Streptococcus pyogenes (very frequent)
TBC (frequent)
Sifilis (rare)
Psittacosis (clamydie infections, not frequent)
Diphtheria (rare)
Leprosy (rare)
Meningococcal Infection (rare)
Yersinia enterolitica
Cat-scratch disease (rare)
Lymphogranuloma venereum (rare)
Virus infections Echo o Coxsackie
Metazoans infestations Filiarosis (rare)
Ascaridosis (rare)
Fungi infestations Blastomycosis (rare)
Coccidioidomycosis (rare)
Histoplasmosis (rare)
Hypersensitivity reaction to drugs Oral contraceptives
Penicillin
Sulfonamide
Other diseases Sarcoidosis (frequent)
Ulcerative colitis (frequent)
Polyarteritis nodosa (rare)
Systemic lupus erythematosus (rare)
Bechcet disease (rare)
TBC, tubercolosis.
Non-commercial use only
acetylsalicylic acid 2-2.5 g/day with gastroprotection misoprostol 400
mg/day; methylprednisolone 16 mg/day per os in the morning to reduce
slowly, to prevent relapse, of about 2.4 mg for once during the first
months and then 1 mg per once every 20/30 days Finnic to the suspen-
sion within 3/6 months; any elastic bandage for edema.
Therapy with oxygen-ozone
Therapy O2-O3must take account of vasculitic component, inflam-
matory and edema of the lesions. The clinical picture suggests the
local therapy as the systemic one, while according to the causes above
mentioned, as shown in the Tables 1 and 2, it can be considered both
the antibacterial, antiviral and immunomodulating action. The abili-
ties to improve the hypoperfusion and hypometabolism, the tissue
ischemia, acute-chronic course of injuries and relapses, suggest pro-
tocols characterized by choices that consider the immunological com-
ponent but also anti-inflammatory and anti-edema ones. The clinical
picture suggests therapeutic choices geared toward systemic treat-
ments with granulomatous amebic encephalitis interspersed by
prostate artery embolization and the local mesotherapy but also with
rectal insufflation (Table 3).
Hypodermitis stasis
The phlebological Hypodermatitis recognizes increased capillary per-
meability, edema and lymphatic stasis as primary causes.4Some forms
also recognize pathological events from the scene of the observable evi-
dence that most of the time are clinically asymptomatic and not yet
manifested, as in cardiocirculatory, liver and kidney diseases. While
others have an acute onset that can be triggered by physical and/or
mental trauma, by exposure to heat or prolonged immobility in a stand-
ing or sitting position, where the lymphatic and venous return is
obstructed by the failure of the muscle or foot pump, or from the wrong
posture. Among the most common causes we can include a diet too rich
in salts, premenstrual syndrome, pregnancy, or taking medicines, espe-
cially for high blood pressure, nonsteroidal anti-inflammatory drugs
(NSAIDS), steroids, estrogens.
In the doldrums the trans capillary passage of proteins (albumin, fib-
rinogen, Ig) is increased. Fibrinogen, which accumulates in large
quantities in the tissue, seems to form true pericapillary sleeves fibrin,
causing an inflammation in macrophage and lymphocyte that is the
basis of pain and inflammation in hypodermatitis.
A certain amount of white blood cells and T-lymphocytes is retained
in the tissue and, for their difficulty in passing through the wall of the
capillary, they remain on site attached to the vessel wall by releasing
the granules containing proteolytic enzymes. In particular, the activat-
ed macrophages that produce IL-1, which stimulates endothelial cells to
produce plasminogen inhibitor activator, may explain the reduced fib-
rinolytic activity, which occurs in patients with chronic venous insuffi-
ciency.4,13 The rheological alteration and dependant modifications of
endothelial cells lead to increased platelet adhesion and activation with
production and release of TNF-α, which is the key cytokine for tissue
repair, whose protracted production determines the development of the
fibrous septa.
The reduced fibrinolytic activity facilitates the precipitation and the
persistence of fibrinogen in the tissue increasing the activity.
After the acute phase, in chronic edema, hypodermitis evolves
towards a phase of retractable fibrosis sclerodermiform affecting the
deep tissues, and the adipose tissue disappears replaced by a dense tis-
sue. Initially the hypodermitis looks like an indurate plate, round or
oval, subcutaneous, supra ankle, adhering to both the surface and deep
plans, painful on palpation. It presents clear signs of inflammation, red-
ness and heat of the skin.
The pain can be spontaneous, even at night, exacerbated by walking
and standing position.
Sometimes the nodules can be spread, which gives the need for a dif-
ferential diagnosis of erythema nodosum. At this stage there is a lack
of phlebitis, infectious complications (erysipelas), even if there are
venous and lymph stasis.4,14 The first symptom is pain on palpation
without appreciable hardening of the part. The concerned segment
presents elastic edema whose result will be hardening, petechial hem-
orrhages, ocher dermatitis, white patches of Milian atrophy and finally
necrotic reactions and the formation of an ulcer maybe as a result of
minor injuries.
In the final stage we see the sclerosing dermatitis, atrophy with pig-
mentary and sclero-hypertrofic leg characterized by a concrete block
dermatitis that holds the ankle in the area where there are calcifica-
tions and subcutaneous ossifications.
Classical therapy
Physical therapy: i) compression bandages - elastic bandage for 3/6
months; ii) daily manual lymphatic drainage followed by a strong com-
pression elastic stockings or compression bandage.
Pharmacological therapy: i) venotropic drugs: diosmin 500 mg×2/day
[page 30] [Ozone Therapy 2016; 1:6270]
Review
Table 3. Prospectus therapy with oxygen-ozone in the erythema nodosum.
Concentration O2-O3 Tecnique Syringe Needle Weekly sessions Total sessions
3-5 μg Local perivenous infiltrations 20 cc 27 g 2/3 12/24/36
50 cc 4 mm
20-40 μg GAE/systemic ossigenation 50 cc / 2 12/24/36
150 cc O2-O3+200 blood + one weekly till the healing of lesions
50-5 μg Topical treatment / / 2/3 12/24
with bag in case of ulcers
10- 20 μg Rectal insufflation 50 cc / 1/2 12/24/36
Om3 long-life water 2-3 glasses/day
Applicate ozoven
Balanced diet rich in flavonoids
Moderate physical activity - walking on a treadmill with orthopedic belt (thickness 3-4.2 mm)
GAE, granulomatous amebic encephalitis.
Non-commercial use only
or oxerutins 1000 mg×2-3/day, or dihydroergotamine 3 mg×3/day; ii)
NSAIDS: nimesulide 100 mg×2/day; or ibuprofen 600 mg×2-3/day.
Periods of 1/2 weeks associated with misoprostol 400 mcg/day; iii) cor-
ticosteroids: betamethasone sodium phosphate 2 mg/day for the first 3
days and then 0.5 mg/day for 4 days.
Surgical therapy: i) permanent discontinuation of the intervention
saphenofemoral, ligation of perforating veins and sclerosing injections;
ii) saphenectomy are in the elderly.
Treatment of infectious complications: antibiotics in pushed lymphan-
gitis that erysipeloid: amoxicillin trihydrate 1g×2/day for at least 10 days.
Therapy of varicose ulcers: i) prolonged rest with leg raised to facil-
itate venous outflow; ii) antibiotics; iii) local dressings with products
such as cadexomer iodine and/or dextran with epichlorohydrin or
dimeticone (Table 4).
Localized lipodystrophy - panniculopathy
edematous fibro sclerotic
Today the misnomer of cellulite includes some blemishes whose
nature and causes require, sometimes, therapeutic intervention of the
doctor. He has the duty to care for the body and also the tissues that
compose it, respecting its integrity and functions without putting in
place practices that can cause pain, damage or cell death. The O2-O3
therapy centers refine these objectives, acting as a medical practice
whose only purpose is to heal and to restore cellular homeostasis and
tissue function.16
For PEFS we mean an alteration of the subcutaneous fat to a regressive
character of unknown etiology. As previously noted in women, the tips of
the lobules, which have a spherical shape, press against the reticular der-
mis and protrude in the form of fat buds characterizing, with a hilly pro-
file, the dermo-hypodermic border. The branches of connective tissue that
surround and hold the lobules are disposed perpendicularly to the skin
level, which, in case of adiposity, conveys the acquired volume to the over-
lying buds, causing uneven skin surface depressions (orange peel skin).15
This benign disease occurs almost exclusively in women and occurs in
all ages, according to the different forms that characterize it. It is localized
predominantly in the anterior-lateral regions of the thighs and calves but
also in the abdominal region and the rear of the arms.
We need to distinguish it from the fatty deposits like pertrochanteric
bearings, due to a mechanical reaction to the gain of body weight, for pro-
longed sitting position, where we can o
bserve a strong accumulation of
fat, with the subversion of the architectural structure of the tissue, the
suffering of the microcirculation, the presence of telangiectasic tufts,
sclerosis of the connective stromal component, sometimes modest
inflammation and in severe cases cold skin for reduced perfusion and
metabolic activity. In cellulitis we can distinguish an inflammatory form,
an edematous, fibro
us and sclerotic. These correspond to the different
developmental stages of suffering and histological tissue. The inflamma-
tory edematous form seems to be typical of young age.
Among the causes that can trigger the phenomena, which lead to the
panniculosis, are the stagnation of the microcirculation, which causes an
increase of albumin protein, fibrinogen and immunoglobulins’ passage.15
The fibrinogen can wrap the capillaries, as a sleeve of fibrin, partially
occluding the pinocytosis channels. This causes the marginalization of
the white blood cells which, for the greater difficulties in which they
deform, pass the wall with difficulty increasing the vascular resistance.
The polymorphic leukocytes attached to the endothelium can be activated
releasing their granules, which contain proteolytic enzymes. The
increased presence of tissue macrophages and T-lymphocytes stimulates
IL-1 production that induces endothelial cells to synthesize plasminogen
activator inhibitor, which may explain the reduced fibrinolytic activity and
which is found in the venous failure.4
Although there isn’t an extensive experimental research, it has been
estimated that the doldrums, the rheological alteration and alteration of
endothelial cells, involve an increase in the phenomenon of adhesion, with
the production and release of TGF-β, which produced in a protracted time,
can determine diffuse fibrosis.15 The reduced fibrinolytic activity facili-
tates the precipitation and the persistence of fibrinogen in the interstitial
tissue, increasing the activity of fibroblasts. After the acute phase, in
chronic edema, hypodermitis evolves toward the retractable fibrosis. The
question that arises is: what is the real state of disease or tissue affliction,
relatively to the aforementioned processes and intensity of symptoms?
To date, the only honest response can be made merely from observation
and experience, as there are no experimental studies and extensive
research on the topic.
Predisposing factors
Among the predisposing factors we include muscular hypotonia, pos-
tural defects, incorrect plantar support, excessive localized fat, disor-
dered lifestyles, unbalanced nutrition with low-protein or hypovitaminic
and low in fiber diet, prolonged standing, use of contraceptives where
estrogens cause an increase in water retention and the patency of capil-
laries, a sedentary lifestyle, obesity.
The muscular hypotonia intervenes negatively on the pump functions
of the arterial and venous vessels accentuating the doldrums in the lym-
phatic system, which does not fully perform the functions of drainage,
[Ozone Therapy 2016; 1:6270] [page 31]
Review
Table 4. Statement of therapy with oxygen-ozone in hypodermitis stasis.
Concentration O2-O3 Tecnique Syringe Needle Weekly sessions Total sessions
3-5 μg Local perivenous infiltrations 20 cc 27 g 2/3 12/24/36
50 cc 4 mm
20-40 μg GAE/systemic ossigenation 50 cc / 2 12/24/36
150 cc O2-O3+200 blood + one weekly till the healing of lesions
50-5 μg Topical treatment / / 2/3 12/24
with bag in case of ulcers
10-20 μg Rectal insufflation 50 cc / 1/2 12/24/36
Om3long-life water 2-3 glasses/day
Applicate ozoven
Balanced diet rich in flavonoids
Moderate physical activity - walking on a treadmill with orthopedic belt (thickness 3-4.2 mm)
GAE, granulomatous amebic encephalitis.
Non-commercial use only
transportation, exchange of nutrients and waste, transport of leukocytes
in lymphatic capillaries, elimination of pathogenic microorganisms, fil-
tration, purification of the lymph and so on.
Postural abnormalities may determine: i) hyperstanding on a limb,
causing muscle contraction and sometimes spasm with changes on the
dynamics of the venous lymphatic circulation, accentuating the phenom-
enon of stasis; ii) incorrect plantar support with cavus (high-heeled
shoes) or flat-footedness of the foot that determines in walking the
wrong pressing of the base of the foot pump with dysfunction of the lym-
phatic venous circulation return.
Another predisposing factor is the sedentary life, the effects of the diet
on the energy balance of the body, for important metabolic and dynamic
meanings on the blood and lymphatic circulation.14,15
The movement in the lower limbs in the veins and lymphatic vessels
is against gravity where the centripetal flow opens the semilunar venous
valves and the centrifugal one closes them.
Venous blood is driven from the periphery to the center by the forces
acting from behind, that is, by the activity of vermicular systolic-diastolic
movements transmitted from neighboring arteries to the vein wall, by
squeezing the Lejard’s venous sole, the muscle pump, by those forces act-
ing from the front represented by the diaphragmatic excursion, which by
compressing and decompressing the intestinal package implements
reflux and suction mechanisms creating negative pressure gradient.
Classification of panniculopathy edematous
fibro sclerotic
Commonly it is used to describe the various stages in the progression
of the formation of cellulite: i) congestive phase: venous and lymphatic
stasis with poor tissue oxygenation, impaired drainage of interstitial
fluids, increase in the volume of adipocytes, and interstitial inflamma-
tion serous, cold skin and edematous; ii) exudative phase: the epider-
mis thins becoming brittle and dehydrated. The suffering of the micro-
circulation increases wit
h the infiltration of polymorph elements nucle-
ated with fibrinous inflammation in the initial phase, micro nodules for-
mation; the skin is slightly reddened in patches;4iii) fibrous phase: per-
sistent inflammation and edema, leakage of fibrinogen generates the
production of fibrin into the gap that represents a powerful stimulus to
the repair by stimulating fibroblasts to lay down collagen fibers, which
determine the beginning of the structural disruption of the tissue with
formation of small adipocyte clusters (nodules),4,15 pain caused by pal-
pation; iv) phase of fibrous scar: you can appreciate subversion of the
lobular structure of the adipose tissue,15 formation of painful nodules on
palpation, sometimes spontaneous pain, even at night, with ankle
edema. The evolution of the disease also leads to symmetrical changes
in the so-called orange peel profile, and skin hypothermia, poor dermo-
graphism, stretch marks and spider veins, feeling of cold, heaviness,
local paresthesia can be detected and also observed.
The alterations of the vessels and blood flow
in panniculopathy edematous fibro sclerotic
The microcirculatory system basically consists of a series of
branched canaliculi, anastomosed with each other, covered with
endothelium, the flow is regulated to arteriolar level at each moment,
only a few capillaries are open, the others remain closed; then, to vary
the flow to the tissue, the true capillaries do not dilate, but open to a
greater number simultaneously.
After a damaging action with inflammation in the microcirculation,
it manifests arteriolar dilation, sometimes preceded by a very short
interval of vasoconstriction, all the precapillary sphincters open simul-
taneously and dilate the postcapillary venules filling quickly with blood
all over the local microcirculation expanding and filling with blood.
Vascular changes, hyperemia and increased blood flow are followed by
the slowing of blood flow, increased intra-vascular pressure, decreased
drainage, increased hydrostatic pressure in capillaries and venules. This
causes a modification of the provision of corpuscular elements in the ves-
sels where the reduced flow speed pushes the red blood cells to assume a
central position, while the white blood cells, especially neutrophils, tend
to set peripherally to the lumen, helping to obstruct the drainage of blood
from the same affected districts causing stasis. The altered vascular per-
meability, the increasing of the hydrostatic pressure and the phenomena
that involve the entire cell population determine exudation with liquid
containing plasma proteins and leukocytes leaking.
Mechanisms of action of oxygen-ozone
in panniculopathy edematous fibro sclerotic
The O3working mechanisms in inflamed tissue stasis of microcircu-
lation, edema and vasculitis-related phenomena are: i) the unsaturated
fatty acid that is related to the double carbon bond transformed into
water-soluble compounds; ii) O3that develops an interaction with the
double bonds of unsaturated fatty acids of the phospholipids in the ery-
throcyte membrane layer by increasing the deformability.5,7 In this way
it reduces blood viscosity and increases the production of 2.3-diphos-
[page 32] [Ozone Therapy 2016; 1:6270]
Review
Table 5. Therapy with oxygen-ozone in lipodystrophies.
Concentration O2-O3 Tecnique Syringe Needle Weekly sessions Total sessions
1-5 μg max Subcutaneous infiltration 50 cc 27 g 2/3 12/24
Hard: 1.5-2.5 5-7 cc point 4 mm or
Soft: 2-3 Max 200 per session 26 g 12 mm
Edematous: 4-5
10-20 μg Rectal insufflation 50 cc / 1/2 12
Ozoil body Lymphatic drainage massage / / 1/2 12/24
release of lymph node stations
Om3 long-life water 2-3 glasses/day
Physical activity immediately after treatment by calculating the heart rate for lipolytic activity
Balanced diet low in sodium
Moderate physical activity - walking on a treadmill with orthopedic belt (thickness 3-4.2 mm)
Sequential pressure air
Non-commercial use only
phoglycerate,5,7,8 responsible for the transfer of O2from hemoglobin to
tissues, with better perfusion and transport along the vascular beds;
iii) O3that exerts anti-inflammatory action by reducing the production
of pro-inflammatory cytokines, immunoglobulins and inflammatory
mediators.5,7-9,11,17,18
Oxygen-ozone therapy in lipodystrophy
For therapy we have to consider the evolution, the vascular impair-
ment, the congestive pain, the edema, the inflammation, and degener-
ative and sclerotic widespread phenomena. We also analyze the tissue
architecture subversion, all factors that characterize the framework
and symptoms, as well as the psychological conditions of the patient,
the weight, muscle tone and nutritional status (Table 5).
Conclusions
With this short dissertation, I have tried to show, through a deduc-
tive reasoning starting from some scientific observations as well as
learning from clinical indications of talented colleagues, how you can
get, in medical practice, a positive experience, but that is certainly not
exhaustive of the subject matter.
References
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