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					Psicothema, 1996. Vol. 8, nº 2, pp. 375-381

                María Angeles Aller*, Laureano Lorente*, Jorge L. Arias**,
         Guillermo Rodríguez-Fabián*, María Soledad Alonso*, Azucena Begega**,
                Laudino López**, José Rodríguez-Gómez***, Jaime Arias*
        * Universidad Complutense de Madrid, ** Universidad de Oviedo, *** Universidad de Zaragoza

               It is proposed that the response of the organism to injury by mechanical energy is ma-
        de up of three consecutive phases: an immediate or nervous phase, an intermediate or im-
        mune phase and a late or endocrine phase. The functions that characterize each one of the-
        se three phases could represent the activity of the functional nervous, immune and endocri-
        ne systems. This functional concept of the psycho-neuro-immune-endocrine system could
        make it possible to integrate biochemical knowledge into the organism response to injury.

               La respuesta psico-neuro-inmune-endocrina en fisiología y patología. Se propone
        que la respuesta del organismo a la agresión por energía mecánica está constituida por
        tres fases consecutivas: una fase inmediata o nerviosa, una fase intermedia o inmune y
        una fase tardía o endocrina. Las funciones que caracterizan cada una de estas tres fases
        podrían representar la actividad de los sistemas funcionales nervioso, inmune y endocri-
        no. Este concepto funcional del sistema psico-neuro-inmune-endocrino permitiría inte-
        grar el conocimiento bioquímico en la respuesta del organismo a la agresión.

   Nowadays, the nervous, immune and en-                learn the interactions that exist between these
docrine systems, which have been conside-               three systems (Lorente et al., 1995).
red as separate “systems” can be considered                 Acute mechanical trauma can produce
components of a single integrated defence               different conditions in the human being,
mechanism in which the interactions betwe-              acute local inflammation and the polytrau-
en systems is as important to understanding             matized patient respectively representing
adaptation as the interaction within a system           its least and greatest severity. The evolution
(Ader, Cohen and Felten, 1995).                         of both conditions can be explained by the
   The study of the response of this single             successive alterations which are produced
integrated defense mechanism of the organism            in the blood vascular endothelium and, by
when it is exposed to an old stimulus such as           extension, in the vascular wall (Lorente et
the mechanical energy, could be a method to             al., 1995). The endothelium, owing to its
                                                        strategic position, plays an exceedingly im-
Correspondencia: Jaime Arias                            portant role in regulating the vascular sys-
Departamento de Cirugía                                 tem by integrating diverse mechanical and
Hospital Universitario San Carlos
C/ Martín Lagos, s/n.
                                                        biochemical signals and by responding to
28040 Madrid (Spain)                                    them through the release of vasoactive subs-


tances, cytokines and growth factors (Inaga-             vasodilation, a second phase, intermediate or
mi, Naruse and Hoover, 1995).                            immune, mediated by the endothelium and
    Different phenomena are successively                 represented by the tissular infiltration of mo-
produced in the local inflammation, which                lecules and blood cells, and a third phase, la-
is considered as a response to post-trauma-              te or endocrine, represented by the cellular
tic necrosis: vasoconstriction and vasodila-             proliferation which, in the case of healing,
tion (Davies and Hagen, 1993), exudation                 involves tissular regeneration or wound re-
secondary to an increase of endothelial per-             pair (Lorente et al., 1995).
meability which is the cause of swelling                    This abstraction also makes it possible to
(Lum and Malik, 1994), diapedesis or cell                consider the evolution of the polytraumatized
migration, specially neutrophils, which is               patient as a succession of three partial res-
associated with phagocytosis and necrosis                ponses (Lorente et al., 1995), that is, imme-
(Adams and Shaw, 1994) and proliferation                 diate or vasomotor, which can produce shock
with endothelium and vascular wall mode-                 (Jacobs and Panic, 1994), intermediate or im-
lling (Davies and Hagen, 1993), which is                 mune, whose hyperexpression represents the
associated with tissular regeneration or                 systemic inflammatory response syndrome
synthesis of granulation tissue.                         (SIRS) (Bone, 1995) and late or endocrine, in
    The succession of vascular changes could             which the predominance of anabolism, con-
represent three phases of the endothelial res-           valescence phase (Shaw and Koea, 1993), or
ponse to injury: a first phase, immediate or             catabolism, with cachetsia (Hassett and Bor-
nervous, characterized by alterations of the             der, 1983; Rennie, 1985), plays the greatest
vascular tone, that is vasoconstriction and              role in its evolution (Figure 1).

Figure 1. The organism, represented by its control (C), mediator (M) and structural (S) components, responds
to injury with inflammation, which is considered as a three successive phases functional response: Immediate
or nervous (N), intermediate or immune (I) and late or endocrine (E), which, in turn, have a hyperfunctional
(+) or hypofunctional (-) expression. C: nervous, lymphoid and endocrine tissue. M: epithelium, endothelium
and mesothelium. S: smooth and striatum muscular tissue, connective tissue, osseous tissue and adipose tissue.

376                                                                                          Psicothema, 1996

   This hypothetical similarity of local and                        (neuro), then the cell adhesion, recruit-
systemic responses, although they have                              ment of mononuclear cells and coagula-
different duration, could be attributed to                          tion predominate (immune) and, finally, a
the existence in the organism of a general                          more delayed response would be characte-
response mechanism to injury by mecha-                              rized by hypertrophy and proliferation of
nical energy, which is based on the suc-                            muscular smooth cells (endocrine) (Da-
cessive and predominant expression by the                           vies and Tripathi, 1993; Davies and Ha-
vascular wall of functions belonging to the                         gen, 1994; Alexander, 1995).
nervous, immune and endocrine systems                                  Furthermore, in the evolution of the hu-
(Lorente et al., 1995) and which could be                           man heart failure the inadequate preserva-
common to other pathological processes in                           tion of Starling’s forces at a microvascular
which this type of energy is involved, such                         level produces an alteration of the endot-
as heart failure and hypertension.                                  helial function that is expressed as an im-
   In arterial hypertension, as a conse-                            pairment of the contractile and vasodilator
quence of the chronic action of physical                            response (neuro), changes in permeability
forces, it would be considered that the en-                         and platelet activation (immune) and an
dothelial cells, the smooth muscular cells                          increased fibrinolytic activity and base-
and the connective tissue of the vascular                           ment membrane thickness (endocrine)
wall first express a rapid vasomotor res-                           (Mahy and Tooke, 1995; Lorente, Aller,
ponse with enhanced vasoconstriction                                Arias, in press a).

                                                             Table I

                                                   Inflammatory Response
                                          LOCAL TRAUMA             POLYTRAUMATIZED             ARTERIAL                     HEART
                                                                       PATIENT               HYPERTENSION                  FAILURE

                             I.           – Vasoconstriction       – Shock (Jacobs et al,   – Enhanced vasocons-      – Impaired contractil
                        Immediate or      (Davies et al, 1993)     1994)                    triction (Davies et al,   and vasodilator res-
                          nervous                                                           1994)                     ponse (Mahy et al,
                                          – Vasodilation (Da-      – Ischemia-reperfu-                                1995)
                                          vies et al, 1993)        sion (Jacobs et al,

                                          – Exudation (Lum et      – SIRS (Bone, 1995)      – Cell adhesion (Da-      – Alteration in capi-
                                          al, 1994)                                         vies et al, 1994)         llary    permeability
                                                                                                                      (Mahy et al, 1995)
                              II.         – Diapedesis (Adams      – MOF (Bone, 1995)       – Recruitment of mo-
                         Intermediate     et al, 1994)                                      nonuclear cells (Da-
     Functional               or                                                            vies et al, 1994; Ale-
      Phases               immune                                                           xander, 1995)

                                          – Coagulation (Da-       – DIC (Bone, 1995)       – Platelet activation     – Platelet activation
                                          vies et al, 1993)                                 (Davies et al, 1994)      (Mahy et al, 1995)

                                          – Fibrinolysis (Davies   – Catabolism (Hasset                               – Increased fibrinoly-
                                          et al, 1993)             et al, 1983; Rennie,                               tic activity (Mahy et
                            III.                                   1985)                    – Hypertrophy and         al, 1995)
                           Late                                                             proliferation of mus-
                             or                                                             cular smooth cells        – Basement membra-
                         Endocrine        – Proliferation:         – Anabolism (Shaw et     (Davies et al, 1994;      ne thickness (Mahy et
                                           • regeneration          al, 1993)                Alexander, 1995)          al, 1995)
                                          • granulation tissue
                                          (Davies et al, 1993)                                                        – Hyalinosis (Mahy et
                                                                                                                      al, 1995)

Psicothema, 1996                                                                                                                       377

   So, the endothelial response to the injury    crine functions, in which case it would be
caused by mechanical energy, the initial in-     considered that the three “classic” organic
sult, could be considered as an old response     systems, that is, nervous, immune and endo-
that essentially represents the consecutive      crine, must necessary be integrated into
and predominant expression of the nervous,       each of the phases of this functional respon-
immune and endocrine functions, which “in        se. This fact implies that each one of these
vivo” are integrated in the response of the      systems is able to collaborate in the expres-
psycho-neuro-immune-endocrine system of          sion of the three above mentioned functio-
the organism (Lorente et al., 1995; Lorente,     nal phases of the organic response to injury
Aller and Arias, in press b). The successive     (Figure 2).
expression by the organism of the nervous,          In addition, different combinations of
immune and endocrine functions in respon-        mediators belonging to the nervous (neuro-
se to the injury by mechanical energy would      transmitters), immune (cytokines) and en-
mean a similarity of the etiopathogenic me-      docrine (hormones) classic systems that
chanisms in pathologies which have been          would predominantly express the functions
considered different up to now because of        that are attributed to each phase could act in
the histologic as well as biochemical diver-     the three phases of this general response to
sity of the structures involved. This hypot-     injury. This would explain the fact that one
hetical integration of different pathological    mediator by itself participates in different
processes caused by mechanical energy into
a functional response made up by three pha-
ses, immediate or nervous, intermediate or
immune and late or endocrine, makes it pos-
sible to consider that all of them represent
different forms of expression of a response
which always has the same meaning, that is,
inflammation (Table I).
   In this sense, bloodletting, a therapeuti-
cal procedure to which Galeno gave great
importance to and which was frequently
used during the middle age, could represent
a method to obtain by a mechanical stimu-
lus, hypovolemics, a systemic neuro-immu-
ne-endocrine response whose effect should
be considered as beneficial in diverse illnes-
ses which produce intense pain and high fe-
ver, although, in contrast, it can also produ-
ce severe complications such as weight loss
and even death.
   The hypothetical similarity of the local
and systemic responses when injury by me-        Figure 2. Functional concept of the nervous (N), im-
                                                 mune (I) and endocrine (E) systems. Function, and not
chanical energy occurs could be attributed
                                                 histology or biochemistry, determines the system that
to the existence in the organism of a general    is expressed in each phase of the inflammatory respon-
response mechanism to injury which is ba-        se. Representative cells of the nervous (a), immune (b)
sed on the successive and predominant ex-        and endocrine (c) systems are capable of expressing
pression of the nervous, immune and endo-        nervous (N), immune (I) and endocrine (E) functions.

378                                                                                   Psicothema, 1996

phases of this response. In this case, the                     lates endothelial regeneration and smooth
functions of each phase of this response                       muscle cell proliferation (Schmidt and Wal-
could be used to propose a functional con-                     ter, 1994; Rodeber et al., 1995).
cept of the nervous, immune and endocrine                         A functional meaning similar to that be-
systems (Lorente, Aller and Arias, in press                    longing to the pluripotential molecules
c) (Figure 2). If the functions which charac-                  would be attributed to the enzymatic sys-
terize each phase define the corresponding                     tems of the organism which make up com-
functional systems of the organism, they                       plex cascades with a great diversity of func-
may similarly make it possible to integrate                    tions. By example, Complement activation
the biochemical knowledge into the func-                       (Baldwin et al., 1995) would be closely re-
tional meaning which each system has.                          gulated at every step of the acute inflamma-
    Multiples molecules which are conside-                     tory response according to the predominant
red as fundamental parts of the living orga-                   function which it expresses in the different
nisms have a multifunctional capacity. Ni-                     phases of the rejection. Thus, in the imme-
tric oxide (NO) stands out among these mo-                     diate phase (neuro), the smooth muscle con-
lecules and it was named “Molecule of the                      traction with vasospasm (C2b, C4a, C3a and
year” by Science in 1992 (Koshland, 1992).                     C5a) would predominate, the intermediate
The continuous and more and more com-                          phase (immune) would be characterized by
plex reviews about NO (Nathan and Xie,                         the increase of vascular permeability (C2b,
1994; Schmidt and Walter, 1994; Kam and                        C3a and C5a), increase of adhesion of ma-
Govender, 1994; Rodeber et al., 1995) are a                    crophages, neutrophils and NK cells (C3b
great challenge when an attempt is made to                     and iC3b), extravascular migration of mo-
integrate its diverse functions into the me-                   nocytes and neutrophils (C5a), with degra-
chanisms that produce most of the physiolo-                    nulation (C3a and C5a) and tissue damage
gical and pathological conditions in the hu-                   from the membrane attack complex (C5b-
man organism. NO is a pluripotential mole-                     C9). Finally, in the late phase (endocrine)
cule which can fulfill the requirements to be                  the endothelial cell release of PDGF and
integrated into the functional neuro-immu-                     bFGF (C5b-C9) with proliferation of fibro-
ne-endocrine response because, in a first                      blasts and smooth muscle cells would pre-
immediate or nervous phase, it is a mediator                   dominate ( Lorente et al., in press).
of analgesia (Nathan and Xie, 1994; Sch-                          Therefore, Complement activation could
midt and Walter, 1994; Kam and Govender,                       express successive and predominant charac-
1994), contraction or relaxation of the vas-                   teristics functions of the nervous, immune
cular smooth muscle (Schmidt and Walter,                       and endocrine systems. In this supposition,
1994; Rodeber et al., 1995), myocardial                        the different functions of the multiple com-
contractility (Rodeber et al., 1995), bron-                    ponents of the Complement could be inte-
chodilation, relaxation of gastrointestinal                    grated into the inflammatory response with
smooth muscle and neurotransmission (Nat-                      a sense that would facilitate the comprehen-
han and Xie, 1994; Schmidt and Walter,                         sion of the implied biochemical mecha-
1994; Rodeber et al., 1995). In the interme-                   nisms. If the components of the Comple-
diate or immune response to injury, this                       ment successively express functions consi-
molecule would be involved in capillary                        dered as nervous, immune and endocrine in
permeability, platelet adhesion and aggrega-                   a way which is similar and simultaneous to
tion and leucocyte adhesion (Schmidt and                       the expression of these functions by the en-
Walter, 1994; Rodeber et al., 1995). And fi-                   dothelium and, by extension, by the vascu-
nally, in the later endocrine phase NO regu-                   lar wall during the inflammatory response,

Psicothema, 1996                                                                                                      379

it may be necessary to enlarge the current        the alveolar space (immune) and a late pha-
concept of the nervous, immune and endo-          se with clearance of intraalveolar fibrin and
crine systems. This would not be limited to       regeneration of alveolar epithelium and ba-
the nervous, lymphoid and endocrine clas-         sement membrane or impaired fibrinolytic
sic systems, but rather all the organism          mechanisms and fibrosis (endocrine) (Si-
would be involved.                                mon and Payne, 1995). If lung inflammation
   These systems would make up a systemic         is considered as a response made up of three
response integrated by the functions consi-       functional phases, it would be possible to
dered characteristic of the nervous, immune       integrate mediators, such as Complement
and endocrine systems (Lorente et al., 1995;      components, arachidonic metabolites, cyto-
Lorente, Aller and Arias, in press b; Loren-      kines, growth factors and hormones, into the
te et al. in press). This functional concept of   functional meaning of each phase.
the systems implies that the cells and bio-           The succession in the expression of the
chemical components of the organism, for          nervous, immune and endocrine functional
example, those which constitute complex           systems by the organism could represent the
enzymatic systems as the Complement, ha-          meaning of an ancestral response whose ef-
ve the property of modifying their functio-       fectivity has made it possible for the orga-
nal expression in the successive phases of        nism to persist on the level of cells, tissues,
response to the injury and, for this reason,      organs and individuals in both physiological
perhaps the characteristic functions of each      situations, that make up the vital cycles as
phase of this response could make it possi-       well as in pathological ones (Lorente et al.,
ble to integrate the current biochemical          1995; Lorente, Aller and Arias, in press a;
knowledge into the evolution of multiple          Lorente, Aller and Arias, in press b). It is
pathological processes and therefore into         tempting to try to establish a comparison
the clinical evolution of the patients (Loren-    between the functional response to the in-
te et al. in press).                              jury of the psycho-neuro-immune-endocri-
   The endothelium is a paradigm in regards       ne system which, in essence, is established
to the cellular pluripotential activity (Davies   on basic functions, such as pain-motility
and Hagen, 1993; Lum and Malik, 1994;             (neuro), intra and extracellular digestion
Adams and Shaw, 1994, Inagami and Naru-           (immune) and anabolism-proliferation (en-
se, 1995). In turn, the endothelial cell makes    docrine) and the vital vegetal and animal
up a functional union with the epithelial cell    cycles in which these functions are also pre-
in order to form multiple organs of the body      dominantly expressed by the living orga-
(kidney, lung, pancreas, liver), which are        nisms in different periods of time (Lorente
functional barriers capable of expressing         et al., 1995; Lorente, Aller and Arias, in
neuro-immune-endocrine functions during           press a).
the inflammatory response. So, in lung in-
flammation, types I and II alveolar epithelial                 Acknowledgements
cells can act together with endothelial cells
and constitute a functional unit (Simon and           We wish to thank the following persons for
Payne, 1995). When there is a noxious sti-        their collaboration: Itziar Aldamendi Gomendio,
                                                  trained nurse at the Hospital Universitario San
mulus, this barrier or unit successively ex-      Carlos, Manuel Espantaleón Agreda, Carlos Bo-
presses an early phase, with vasoconstriction     bo San Gil and Benito Sánchez Quintana, libra-
and vasodilation (neuro), an intermediate         rians of the Hospital Universitario San Carlos Li-
phase with alveolar swelling and accumula-        brary and Barbara Shapiro, who translated this
tion of fibrin and inflammatory cells within      article into English.

380                                                                                 Psicothema, 1996


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Lorente L., Aller M.A., Rodriguez-Fabián G.,
   Alonso M.S., Durán H.J., Arias J.L., Begega                                                 Aceptado el 13-2-1996

Psicothema, 1996                                                                                                      381