The role of inflammatory response and pain pathways in

JUSTUS- LIEBIGUNIVERSITÄTGIESSEN

Klinik und Poliklinik für Urologie und Kinderurologie

Klinik und Poliklinik für Urologie und KinderurologieUniversitätsklinikum Gießen und Marburg GmbH

- Standort Gießen -Justus-Liebig-Universität Gießen(Direktor: Prof. Dr. W. Weidner)

The role of inflammatory response andpain pathways in prostatitis

FME Wagenlehner

1. Acute bacterial Prostatitis

2. Chronic bacterial Prostatitis

3. Chronic Pelvic Pain Syndrom (CPPS)

3a. inflammatory

3b. non-inflammatory

4. Asymptomatic Prostatitis

NIH-Classification of the Prostatitis syndrome

National Institutes of Health: Chronic Prostatitis Workshop, Bethesda, Maryland, USA, 7.-8. Dez. 1995

1. Acute bacterial Prostatitis ∼ 0,1%

2. Chronic bacterial Prostatitis ∼ 1%

3. Chronic Pelvic Pain Syndrom (CPPS) ∼ 10%

3a. Inflammatory ∼ 2%

3b. non-inflammatory ∼ 8%

4. Asymptomatic Prostatitis ∼ 90%

NIH-Classification of the Prostatitis syndrome

National Institutes of Health: Chronic Prostatitis Workshop, Bethesda, Maryland, USA, 7.-8. Dez. 1995

1. Acute bacterial Prostatitis ∼ 0,1%

2. Chronic bacterial Prostatitis ∼ 1%

3. Chronic Pelvic Pain Syndrom (CPPS) ∼ 10%

3a. inflammatory ∼ 2%

3b. non-inflammatory ∼ 8%

4. Asymptomatic Prostatitis ∼ 90%

NIH-Classification of the Prostatitis syndrome

National Institutes of Health: Chronic Prostatitis Workshop, Bethesda, Maryland, USA, 7.-8. Dez. 1995

1. Acute bacterial Prostatitis ∼ 0,1%

2. Chronic bacterial Prostatitis ∼ 1%

3. Chronic Pelvic Pain Syndrom (CPPS) ∼ 10%

3a. inflammatory ∼ 2%

3b. non-inflammatory ∼ 8%

4. Asymptomatic Prostatitis ∼ 90%

NIH-Classification of the Prostatitis syndrome

National Institutes of Health: Chronic Prostatitis Workshop, Bethesda, Maryland, USA, 7.-8. Dez. 1995

CP/CPPS and clinical characteristics

40Sexual

63Abdominal

68Urinary

82Pain

%/ 764Symptoms

Bartoletti R et al., 2007 (Italian Prostatitis Study Group)

Pain

International Association for the study of pain, 1994

Unpleasant sensory and emotionalexperience associated with actual or

potential tissue damage, or described interms of such damage.

Pain

Protective response to tissue injury

Persistent pain is maladaptive

Chronic Pain

International Association for the study of pain, 1994

Pain that persists past the healing phasefollowing an injury.

Pain

• Acute 0 – 7 days

• Subacute 7 days – 3 months

• Chronic > 3 months

Pain characteristics

• Stimulus-evoked– Hyperalgesia (noxious stimulus)– Allodynia (non-noxious stimulus)

• Stimulus-independent– Burning– Paresthesia

Pain pathophysiology

• Nociceptive– Associated with tissue damage

(inflammation)• Neuropathic

– Associated with lesions in the nervous system(peripheral/ central)

• Mixed– Nociceptive + neuropathic

EAU guidelines 2008

Inflammation is the basic processwhereby tissues of the body

respond to injury

Immune system: basic principles• Innate (natural) system

– Responses always to same extent– Recognizes a few (10³) highly

conserved structures• Cells

– Phagocytic cells• Neutrophils• Monocytes• Macrophages

– Cells with inflammatory mediators• Basophils• Mast cells• Eosinophils

– Natural killer cells• Molecular components

– Complement proteins– Acute-phase proteins– Cytokines

• Acquired (adaptive) system– Responses improved on repeated

exposure– Recognizes multiple antigens (>107)

• Cells– Antigen-presenting cells

• Dendritic cells• Macrophages• B-lymphocytes

– Antigen-specific cells• B-lymphocytes• T-lymphocytes

• Molecular components– Antibodies– Cytokines

Thacker MA et al., 2007

Mendell JR et al., NEJM 2003

Apkarian AV et al. 2008

Chronic back pain

Post herpetic neuralgia

Pelvic pain (visceral pain)Osteoarthritis

Post herpetic neuralgia

Healthy acute pain

Nerves in the prostate

Doll A., Barcelona

Cytokines and chemokines in CPPS

• No correlation with most mediators• Macrophage inflammatory protein-1a (MIP-1a)

– Chemotactic and activating activity for macrophages– Elevated in rheumatoid arthritis, ulcerative colitis– role in inflammation-induced hyperalgesia

Desireddi NV, AJ Schaeffer et al., 2008

MIP-1a levels in EPS

Desireddi NV, AJ Schaeffer et al., 2008

CPSI pain score and MIP-1a

Desireddi NV, AJ Schaeffer et al., 2008

Autoimmune prostatitis in mice

•Von Frey filaments•Stimulation 10x•Response frequency

Rudick CN et al., 2008

Rat prostate suspension

Rudick CN et al., 2008

Inflammation scores

Control mice Autoimmune prostatitis mice

Rudick CN et al., 2008

Autoimmune prostatitis in mice

Rudick CN et al., 2008

Autoimmune prostatitis miceControl mice

Increased prostate neurite density

Rudick CN et al., 2008

Mast cells and nerves

Bunnett NW 2006

STIMULUS Mast CellsActivation

(Degranulation)

Cytokines PAR-2 Receptor

Pain spinal cord sensoricnerves(CGRP)

Aumüller and Meinhardt, 2002

Hypothesis of pain in CP/CPPS

Conclusion

• Pain most important symptom in CP/CPPS• Prostate inflammation can cause chronic

pain• Inflammation needs further characterisation• Causes need further study• Potential therapeutic targets

Liang R et al., 2007

Organ crosstalk

control

colitis

Liang R et al., 2007

control colitis

Thacker MA et al., 2007