Article Type : Research Article
Authors : Lissoni P, Rovelli F, Fumagalli L, Monzon A, Messina G and Di Fede G
Keywords : ARDS; Cannabinoids; Coronavirus; COVID-19; Melatonin; Pineal gland; SARS
Irrespectively of its specific cause, ARDS represents one of
the most severe complications, and it has been proven to be due to an absolute
profound alteration involving several cytokine secretions, which are depending
on an exaggerated immunoinflammatory biological response of patients rather
than on the direct action of pathogenic agent itself. The most common
ARDS-related cytokine profile is consisting of abnormally high blood levels of
TNF-alpha, IL-6, and IL-17A, by realizing a concomitant occurrence of both
macrophage- and TH17-mediated inflammatory processes. The abnormal cytokine
secretions could be potentially controlled through three essential strategies,
represented by the administration of monoclonal antibodies against some
specific cytokines, the administration of other cytokines with antagonistic
effects, and in a new manner a pharmacological neuroimmune manipulation of the
cytokine network. Because of their fundamental physiological role in the
neuroimmunomodulation and their complete lack of toxicity, the pineal hormone
melatonin and cannabinoid agents could constitute the more appropriate drugs.
The recent advances in the knowledge of the
physiopathology of human systemic diseases have demonstrated that the
immunoinflammatory biological response is under a central regulation [1], which
is mediated by a great number of proteins, the so-called cytokines, namely
released from the activated immune cells. Most cytokines have received the
definition of interleukins (ILs), and at present the number of proteins
classified as interleukins is 40 [2]. In addition to the proteins defined as
interleukins, we have to consider at least some other cytokines provided by a
fundamental role in the regulation of the biological response, namely TNF-alpha
[3] and TGF-beta [4], respectively characterized by an inflammatory, or an
anti-inflammatory activity, even though they are both provided by a common
immunosuppressive action, atleast in the anticancer immunity. The secretion of
the different types of cytokines substantially depends on the interaction
between macrophage and lymphocyte systems, particularly by the T lymphocytes.
Several T lymphocyte subsets have been discovered, but from a clinical point of
view the regulation of the immune system would mainly depend on three
fundamental subpopulations of T cells, which may be recognized on the basis of
the different types of molecules expressed on their cell surface, the so-called
clusters of differentiation (CDs), and which consist of T helper (TH)
lymphocytes (CD4+), regulatory T (T reg) lymphocytes (CD4+CD25+), and TH17
lymphocytes (CD4+CD17+). TH cells may be furtherly classified into TH1 and TH2
cells, not in relation to a different CD expression, but only in relation to
the different type of cytokines produced by them. TH1 cells release IL-2,
gamma-interferon (IFN) and IL-21, whereas TH2 mainly produced IL-4, IL-5, IL-6,
IL-10 and IL-13. T reg cells may secrete TGF-beta, IL-10, IL-22, and IL-35,
while TH17 have been proven to secrete IL-17, which exists in six isoforms; the
most biologically active of them is IL-17A [5]. On the other side, the
classification of macrophages is more undefined, even though they are generally
subdivided into M1 and M2 macrophages, respectively characterized by a major
inflammatory and anti-inflammatory activity [6]. As far as the biological
function of interleukins is concerned, it has been shown that most of them are
characterized by an inflammatory activity, which, however, has appeared to be
due to different mechanisms. The group of cytokines provided by inflammatory
activity includes IL-1 beta, IL-6, IL-17, IL-18, IL-20, IL-22, IL-23, IL-24,
IL-32, IL-36, and IL-38 [2]. Moreover, it has been demonstrated that some
interleukins generally classified as anti-inflammatory cytokines on the basis
of their in vitro effects [2], have appeared in vivo to induce an inflammatory
status, such as IL-4 and IL-13, because their stimulatory effect on histamine
release, with a consequent possible development of a capillary leak syndrome
[7]. Other interleukins, namely IL-2, IL-12, IL-15, and IL-21, may exert both
inflammatory and anti-inflammatory effects, depending on their dosage and on
the different experimental and clinical conditions [8]. On the other side, the
number of interleukins provided by a clear anti-inflammatory effect is very
low, and it is substantially limited to IL-10 [9], IL-30, IL-35, and IL-37 [2].
IL-10 is namely produced by T reg lymphocytes, as well as TGF-beta [4,9]. In
addition, more recently it has been identified the existence of at least two
different origins of the inflammatory status [10], represented by the
macrophage system namely through the release of IL-1 beta, IL-6, IL-18, and
TNF-alpha, and by the lymphocyte system, due to TH-17 cells through the
secretion of IL-17 [5]. Obviously, lymphocyte-related inflammation is a more
recent form of inflammation with respect to that mediated by the macrophage
system from a phylogenetic point of view. Macrophage-mediated inflammatory
status is more typical of the advanced metastatic diseases [11], while that
induced by TH17 lymphocytes would represent the type of inflammation characterizing
the autoimmune diseases [12]. IL-2 has appeared to counteract TH-17
differentiation and IL-17 production, and this IL-2 activity is inhibited by
IL-1 beta [12]. Then, IL-1 beta, as well as IL-6 and IL-23, contributes to
stimulate TH17 cell functions. Therefore, at present it is known that the
inflammatory status, which characterizes each severe systemic human disease
would be due to different types of interaction occurring between macrophage and
lymphocyte systems, since the functionless of immune system itself may be
synthetically interpreted as the end-result of macrophage-lymphocyte
relationships. The whole system of cytokines constitutes the cytokine network,
whose great complexity is mainly depending on the fact that several cytokines
are connected among them by positive feedback mechanisms, then by reciprocal
stimulatory circuits. The systemic human diseases would be substantially due to
unbalanced ratios among the three major T cell subsets, consisting of TH1-to-T
reg cell ratio [13], TH17-to-T reg cell ratio [14], and, even though with less
importance, TH1-to-TH17 cell ratio. The metastatic cancer is characterized by a
progressive decrease in TH1-to-T reg cell ratio [13], while the autoimmune
diseases are characterized by an abnormally high TH17-to T reg cell ratio [14].
Macrophage-related chronic inflammation, which characterizes the advanced
neoplastic diseases [15], may be clinically identified by the evidence of
abnormally high blood levels of TNF-alpha and IL-6, as well as by an abnormally
low lymphocyte-to-monocyte ratio (LMR) [16]. On the other side, TH17
lymphocyte-related inflammation, which is responsible for the pathogenesis of
the autoimmune diseases, is clinically recognized by the occurrence of
abnormally high blood concentrations of IL-17 [17], as well as by a normal or
enhanced LMR, at least during the remission phase of disease [16]. Finally, it
has been well documented that the cytokine network is physiologically under a
central neuroendocrine regulation, which is the expression of the
psychospiritual life [18], namely realized by the pineal gland [19,20] through
the circadian light/dark release of several indole and beta-carboline
neurohormones, the most investigated of them is the indole hormone melatonin
(MLT) [19,21]. The pineal gland plays its immunostimulatory and
immunoregulatory role namely in connection with brain cannabinoid system [22],
while the brain mu-opioid system would exert a major immunosuppressive activity
[23].
The acute respiratory distress
syndrome (ARDS), which includes the severe acute respiratory syndrome
(SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, represents one of
the most severe clinical complications, which may occur during lung injury, disseminated
cancer, or coronavirus infection. Despite the different causes, ARDS would be
due to similar mechanisms, consisting an abnormal and excessive inflammatory
cytokine endogenous secretion, namely that of TNF-alpha [24] and IL-6 [25].
Then, ARDS would mainly depend on host biological immunoinflammatory response,
namely mediated by the macrophage system, rather than to a direct action of
some specific cause. In any case, more recently it has been shown that
TH-17-related inflammation is also involved in ARDS [26]. In more detail, it
has been shown that the concomitant occurrence of a TH-17 lymphocyte-related
inflammation in patients with ARDS, as shown by the evidence of abnormally high
blood concentrations of IL-17A, as well as by an evident increase in TH17-to-T
reg cell ratio (TH17/T reg), may allow a more severe and often lethal prognosis
[26]. This evidence may be simply explained by the fact that a decline in the
functionless of T reg cell system would allow a more severe host inflammatory
reaction. Then, if we consider that macrophage-related inflammation is more
typical of the metastatic tumours [11,15], while TH-17-related inflammation is
namely involved in the autoimmune diseases [12,14], it appears that
ARDS-related inflammatory status could be imaginatively considered as the
synthesis of the clinical complications of both metastatic cancer and
autoimmune disorders in their exacerbation phase. Therefore, the clinical
evolution of ARDS would have to be monitored by detecting LMR values, TH17/T reg
cell ratio, and blood levels of TNF-alpha, IL-6, IL-10, and IL-17A. The
histopathological examination of lungs in patients with coronavirus-induced
ARDS shows oedema, proteinaceous exudate with globules patchy inflammatory
cellular infiltration and formation of hyaline membranes, diffuse alveolar
damage, and pneumocyte desquamation [27]. The clearly higher mortality of aged
patients during viral infections, including the COVID-19 one, could be namely
due to age-decline in the functionless of the immune system, consisting of
progressive increase in TH17 cell [28] and decline in T reg cell counts [29],
with a following increase in TH17/T reg cell ratio, which allows a greater risk
of ARDS in the case of lung injury or lung viral infections. On the contrary,
children are less resistant to ARDS development at least in part because of
their higher blood levels of MLT itself [21].
Being due to a profound
alteration in the endogenous production of cytokines, it is obvious that the
cure of ARDS would have to consist of a modulation of the cytokine network. One
way is represented by the administration of monoclonal antibodies against those
cytokines, whose secretion are abnormally increased, such as Certolizumab for TNF-alpha,
and Tocilizumab for IL-6, but the complexity of cytokine alterations makes as
difficult a similar approach. ARDS-related TH17 cell abnormal activation could
be counteracted by IL-2 itself, since IL-2 has been proven to inhibit TH17 cell
system [12], but its potential inflammatory action could furtherly negatively
influence the clinical course of ARDS, even though low-dose IL-2, which may be
well tolerated [8], might allow a decline in TH17/ T reg cell ratio by
activating T reg cell system and inhibiting TH17 cell hyperfunction, with a
consequent possible improvement of the prognosis of ARDS itself. Another simple
and non-toxic strategy to modulate host immunoinflammatory reactivity in an
inhibitory way may be drawn from the recent advances in the psycho-neuro-endocrine-immunology
(PNEI) [18]. In fact, it has been shown that the inflammatory status induced by
both macrophage and TH17 cell system hyperactivation may by blocked through a
neuroendocrine approach, with a consequent possible inhibition at least in part
of TNF-alpha, IL-6 and IL-17 secretions. In more detail, according to the
knowledgements of PNEI, the secretion of both TNF-alpha and IL-6 may be
counteracted by the pineal hormone MLT [30,31], while that of IL-17 may be
blocked by the non-psychotic agent of Cannabis, the cannabidiol (CBD) [32], or
by its endogenous equivalent palmitoyl-ethanol-amide (PEA) [33]. CBD is not a
CB1-CB2 agonist, but it may inhibit the activity of the main enzyme involved in
cannabinoid destruction, the fatty acid amide hydrolase (FAAH), with a
following possible increase in brain cannabinoid endogenous content [34,35]. In
addition, MLT has also been proven to reduce the clinical severity of most
viral infections in experimental conditions, including various encephalitis
viruses, Ebola virus, and COVID-19 itself [31,36]. Finally, MLT has also
appeared to counteract TGF-beta -induced fibrosis following tissue damage [37].
The clinical advantage of MLT is in its completely lack of toxicity even at
very high pharmacological doses, corresponding to 1mg/day in healthy subjects
[38] and 100 mg/day in very compromised metastatic cancer patients [39].
Obviously, dosage and schedule of treatment may be established only by clinical
investigations. Finally, the ARDS-related cardiopathy could achieve some
benefits from oxytocin therapy, because of its cardioprotective activity and
its important role in heart regeneration either alone, or by stimulating atrial
natriuretic peptide (ANP) secretion, which is also provided by cardioprotective
effects [40].