sh – m – m – t

Papiro 1650 A.C.

 INFLAMACION
La inflamación puede entenderse como un extremo abanico de respuestas innatas y adaptativas con las que el
organismo confronta los retos y perturbaciones a la homeostasis tisular, cualquiera que sea el origen de éstas injurias.
Es posible llegar a dicho extremo de modo paulatino o inmediato, de acuerdo con las características del reto y del
propio organismo.
Irritantes químicos

Físicos
Agente
agresor Isquemia

Reacción Inmune

Infección
 INFLAMACION

Agresión
Aislar al
agresor

Respuesta Destruir al
agresor
Inespecífica
Reparar los
tejidos
 INFLAMACION
Agentes biológicos
(Virus, Bacterias, Hongos, NOD, RIG
RAGE, P2X7
Protozoarios, Helmintos)

Mol. Hidrofóbicas
DNA, RNA, ADP,
Agentes Físicos
(Luz UV, calor, frío, trauma)
Ac. Úrico, HSP
Inflamasoma
Agentes Químicos
(Ácidos, SO2, NO2, O3)

Necrosis
Eventos
vasculares
(Isquemia, Infarto, Hipoxia)
Hipersensibilidad
(iROs, LTC4, MBP, ECP)
 Hipótesis de la COX
En 1971 demuestra que los fármacos similares a la aspirina
actúan por inhibición de enzimas que sintetizan
prostaglandinas, además sugiere que esta inhibición es la
base de su acción analgésica.

Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action

for aspirin-like drugs.
Nat New Biol 1971 Jun 23;231(25):232-5
 CONTROVERSIAS CLINICAS SOBRE LA
HIPOTESIS DE LA COX UNICA EN CUANTO
A SU EFECTO ANTIINFLAMATORIO

La cantidad de aspirina necesaria Aspirina para inhibir

COX es muy pequeña en relación a la dosis que se
requiere para producir efecto antiinflamatorio.
 Hipótesis del Papel exclusivo
del COX2
Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P
The induction and suppression of prostaglandin H2
synthase
(cyclooxygenase) in human monocytes.
J Biol Chem 1990 Oct 5;265(28):16737-40
Hipótesis del Papel exclusivo
del COX2
ESTIMULOS FISIOLOGICOS ESTIMULOS INFLAMATORIOS

COX-1 COX-2
constitutiva inducida

TxA2 PGI2 PGE2 Células

Plaquetas Endotelio Riñon Inflamatorias
Estómago
Mucosas PGs

INFLAMACION
Cell 1995 Nov 3;83(3):483-92
Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced
inflammation and indomethacin-induced gastric ulceration.
Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Mahler JF, Lee CA, Goulding
EH, Kluckman KD, et al

Cyclooxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis and the target
enzymes for the widely used nonsteroidal anti-inflammatory drugs. To study the physiological roles of the
individual
Los ratonesisoforms,
mutantes
wehomocigotos
have disrupted
dethe
Ptgs1
mouse
sobreviven
Ptgs1 gene
bien,
encoding
no tienen
COX-1.
patología
Homozygous
gástricaPtgs1
y muestran
mutant
mice survive
menos ulceración
well, gástrica
have no inducida
gastric pathology,
por indometacina
and showque
lesslos
indomethacin-induced
ratones de tipo salvaje,
gastric
aunque
ulceration
sus
than wild-type
niveles de prostaglandina
mice, even E2
though
gástrica
their
songastric
aproximadamente
prostaglandinelE21%
levels
de los
arede
about
tipo 1%
salvaje.
of wild
Lostype.
ratones
The
homozygous
mutantes homocigotos
mutant micetienen
have reduced
una agregación
platelet aggregation
plaquetariaand
reducida
a decreased
y unainflammatory
respuesta inflamatoria
response to
arachidonicalacid,
disminuida ácido
butaraquidónico,
not to tetradecanoyl
pero no al
phorbol
acetatoacetate.
de tetradecanoil
Ptgs1 homozygous
forbol. mutant females mated to
homozygous mutant males produce few live offspring. COX-1-deficient mice provide a useful model to
distinguish the physiological roles of COX-1 and COX-2.
Cell 1995 Nov 3;83(3):473-82
Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse.
Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, Mahler JF, Kluckman
KD, Ledford A, Lee CA, et al

The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is induced at high

levels in migratory and other responding cells by pro-inflammatory stimuli. COX-2 is generally
considered to be a mediator of inflammation. Its isoform, COX-1, is constitutively expressed in most
tissues and is thought to mediate "housekeeping" functions. These two enzymes are therapeutic
targets of the widely used nonsteroidal anti-inflammatory drugs (NSAIDs). To investigate further the
different physiologic roles of these isoforms, we have used homologous recombination to disrupt the
mouse gene encoding COX-2 (Ptgs2). Mice
Los lacking COX-2
ratones que havedenormal
carecen inflammatory
COX-2 tienen respuestasresponses to
inflamatorias
normaleswith
treatments a los tx. con acetato dephorbol
tetradecanoyl tetradecanoil forbol
acetate or owith
con ácido araquidónico.
arachidonic acid. However, they develop
severe nephropathy and are susceptible to peritonitis.
Essentials of Medical Pharmacology Eighth Edition
RETIRADO NO APROBADO POR LA FDA
RIESGO CARDIOVASCULAR RIESGO GASTROINTESTINAL
 ACETAMINOFEN
DICLOFENACO
LUMIRACOXIB
 The New England Journal of
Medicine
Vol. 336(15) Apr 10, 1997 pp 1066-1071
Mechanisms of Disease: Nuclear Factor-
(kappa)B -- a Pivotal Transcription Factor
in Chronic Inflammatory Diseases.
Barnes, Peter J.; Karin, Michael.
 Mecanismo de Activación del NF-κB
Estímulo
Complejo NF-κB

p65
p50

IκBK
F F
IκB
p65
IκB p50
P65 IκBde
p50

p65
p50
Proteínas
inflamatorias

Sitio unión NF-kB

GENES PROINFLAMATORIOS
https://www.cellsignal.com/pathways/nfkb-signaling-pathway
 Science
Volume 265(5174) August
12, 1994 pp 956-959
Inhibition of NF-kappa B by
Sodium Salicylate and Aspirin
Kopp, Elizabeth; Ghosh Sankar.

The transcription factor

nuclear factor-kappa B (NF-
kappa B) is critical for the
inducible expression of
multiple cellular and viral
genes involved in
inflammation and infection
including interleukin-1 (IL-1),
IL-6, and adhesion molecules.
The anti-inflammatory drugs
sodium salicylate and aspirin
inhibited the activation of NF-
kappa B, which further
explains the mechanism of
action of these drugs.
 Science
Vol. 270(5244):2017-2018; 1995
The Effect of Sodium Salicylate
and Aspirin on NF-kappa B
Frantz, Betsy; O'Neill, Edward A.
Elizabeth Kopp and Sankar Ghosh
find that activation of the
transcription factor nuclear factor-
kappa B (NF-kappa B) is inhibited by
aspirin and salicylate, which
suggests an explanation for the anti-
inflammatory nature of these drugs
(1). Because the conclusion has
significant implications for the
development of novel anti-
inflammatory agents, we explored
the phenomenon further. We found
that at concentrations required for
inhibition of NF-kappa B-dependent
transcription, sodium salicylate
inhibits activation of a variety of
transcription factors. This appears
to result from the ability of
salicylate to nonspecifically
inhibit cellular kinases.
TEJIDO SANO TEJIDO INFLAMADO
 HIPOTESIS DE ABRAMSON Y WEISSMANN

Generación
de Radicales
Libres

FLC

RECEPTOR
X PIP2

Proteínas G
IP3
DAG
Señales
Ca+
PKC
Liberación
de
Gránulos

Adhesión
E
S Célula-Célula
T
I
M
U
L
O
 Inhibition of Leukocyte Adhesion:
an alternative mechanism of action for anti-inflammatory drugs.
Díaz-Gonzalez F. and Sánchez-Madrid F.
Immunology Today Vol.119(4):169-172; 1998

ACTIVATION
2

Inhiben 1: Inhiben 2:
Acelofenaco, Aspirina, Diclofenaco, Nimesulida, piroxicam, meloxicam,
Indometacina, Acido Mefenámico, fenilbutazona.
Acido Flufenámico
 LOS AINES NITRADOS DERIVADOS:

La GASTROPROLESION por AINES un problema de

contracción vascular?

Nitroaspirina
Nitroflurbiprofeno

Presentan en su estructura un radical nitrobutilester.

Control 05 Control 06

Estómago de Ratas Tto con Aspirina

Tto Aspirina+Di - Animal 17 Tto Aspirina+Di - Animal O7

Animales con Tto de protección por DI

 Bacteria vs Neutrófilo

Fagocitosis: Quimiotaxis g Adherencia g Endocitosis g Digestión

g Respuesta rápida
g Respuesta lenta
Muchas moléculas y células eficientemente
coordinadas en 2 formas de respuesta:
 Familia de los Toll-like receptor (TLR) de
Receptores de Reconocimiento de Patrones

Peptidoglican (G+)
Lipoproteina
Lipoarabinomananos
Zimosan (Hongos) LPS(G-) CpG AND
Proteina GPI RSV F dsRNA Flagelina Bacteriano

TLR-6 TLR-2 TLR-1 CD14 MD-2 TLR-4 TLR-3 TLR-5 TLR-9

Nat. Rev. Immunol. 2001; 1: 135

 ReceptoresToll-Like y sus Ligandos

Receptor Ligando (PAMPs) Origen del Ligando

TLR1 Triacyl lipopetides Bacteria and Mycobacteria
Soluble factors Neisseria meningitidis
TLR2 Heat Shock protein 70 Host
Peptidoglycan Gram-positive bacteria
Lipoprotein/lipopeptides Various pathogens
HCV core and nonstructural 3 protein Hepatitis C Virus
TLR3 Double-stranded RNA Viruses

TLR4 Lipopolysaccharides Gram-negative bacteria

Envelope protein Mouse mammary-tumor virus
Taxol Plants
TLR5 Flagellin Bacteria

TLR6 Zymosan Fungi

Lipoteichoic acid Gram-positive bacteria
Diacyl lipopetides Mycoplasma
TLR7 Single-stranded RNA (ssRNA) Viruses
Imidazoquinoline Synthetic compounds
TLR8 Single-stranded RNA (ssRNA) Viruses
Imidazoquinoline Synthetic compounds
TLR9 CpG-containing DNA Bacteria, Malaria and Viruses

TLR10 Not determined Not Determined

TLR11 Profilin-like molecule Toxoplasma gondii

To l l l i k e r e c e p t o r s ( T L R )
Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL.
Two types of murine helper T cell clone. I. Definition according to
profiles of lymphokine activities and secreted proteins. J Immunol.
1986;136:2348–2357.
Human Th1 and Th2 subsets: doubt no more.
Sergio Romagnani
Immunol-Today. 1991 Aug; 12(8): 256-7
 IL-12
Linfocitos CD4+ (+) IFN-
TCR / IL-2
LT
Th1 IFN-γ

IL-2,IL-4
Precursor
CD4+ (IFN-) (-) IL-4

Thp Thp’ Th0

IL-4*
(+) IL-4 IL-5*
IL-6
IL-2 IL-2 IL-9
IL-10
Th2 IL-13*
IL-25
“Paradigma de las subpoblaciones linfocitarias” (-) IFN-
 Balance Inmune

TH-1 TH-2
Disbalance Inmune Th1

TH-2

TH-1

IL-12
Disbalance Inmune Th2
IL-4 IL-10
TH-1

TH-2
 IL-12
Linfocitos CD4+ (+) IFN-
TCR / IL-2
LT-alfa*
Th1 IFN-*

IL-2,IL-4
Precursor
CD4+ (IFN-) (-) IL-4
TGF-
Suprimer Th1
Thp Thp’ Th0 Th3 y Th2

(+) IL-4 IL-4*

IL-5*
IL-6
IL-2 IL-2 Th2 IL-9
Tr1 (-) IFN-
IL-10
Tr IL-13*
IL-25
IL-10
CD4+
Th17 Th9 IL-31
TGF-
CD25+ Auto Hipers.
Inmunidad Alergica
Regulación Th1/Th2 x Treg

Treg
Una nueva regulación Th1/Th2 x
TregxTh17?

Th17
Th22
Célula

Ambiente

Diferenciación

Resultado

Th1 Th17 Th2 Treg

Inflamasoma
NF-kB
IL-1
IL-18

Resolución
https://researchfeatures.com/wp-content/uploads/2017/06/Professor-Charles-N-Serhan-Harvard-Medical-School-Molecular-Pharmacology.pdf
https://researchfeatures.com/wp-content/uploads/2017/06/Professor-Charles-N-Serhan-Harvard-Medical-School-Molecular-Pharmacology.pdf
Circ Res. 2010;107:1170-1184
Circ Res. 2010;107:1170-1184
Insert F01-06
 Hipótesis de John R. Vane (Inhibición de las COXs)
1971 Inhibition of prostaglandin synthesis as a mechanism
of action for aspirin-like drugs.
Nature New Biol. 1971;231:-235.

Hipótesis de S.B. Abramson y G. Weissmann (activación y adhesión)

1989
The mechanism of action of nonsteroidal antiinflammatory drugs
Arthritis & Rheumatism 32(1):1-9; 1989

Hipótesis de P. Needleman (COX1-COX2)

J Biol Chem 1990 Oct 5;265(28):16737-40
1990 The induction and suppression of prostaglandin H2
synthase (cyclooxygenase) in human monocytes.
Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P

Hipótesis de E. Kopp y S. Ghosh (Glucocorticomimética)

1994 Inhibition of NF-kappa B by Sodium Salicylate and Aspirin
Science Volume 265(5174) August 12, 1994 pp 956-959

Hipótesis de X. A. Wang (Quelación de cationes divalentes)

1998 A chelate theory for the mechanism of action of aspirin-like drugs.
Medical Hypothesis 1998;50(3):239-251.
 The Lancet
Volume 353(9163) May 1, 1999 p 1503
COX-2 inhibitors take one step forward-and one back
Ault, Alicia

In osteoarthritis efficacy trials, rofecoxib once-daily was compared with

placebo, and with ibuprofen 800 mg three times daily or diclofenac 50 mg
three times daily. Rofecoxib fue comparable a los AINES como lo fue
en los ensayos de dolor agudo. In gastrointestinal studies, patients
were given 25 mg or 50 mg of rofecoxib or 2400 mg of ibuprofen daily and
examined endoscopically. At 12 weeks, 4.7% and 8.1% of patients
given low-dose and high-dose rofecoxib, respectively, had a
gastroduodenal ulcer bigger than 3 mm, compared with 28.5% of
patients given ibuprofen. However, the FDA said that
rofecoxib (and celecoxib) must carry the same warning
as NSAIDs-that gastrointestinal damage could occur at
any time.