NEW INSIGHTS INTO PATHOGENESIS OF UIP/NSIP

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NEW INSIGHTS INTO PATHOGENESIS OF UIP/NSIP

• Dr. Derya Gumurdulu
• Cukurova University, Faculty of Medicine,
  Department of Pathology, Adana

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Interstitial lung disease

• Interstitial inflamation and/or fibrosis
• 30 etiology
• 70 idiopathic
• Open lung biopsy
• Communication between the pathologist and
  clinical and radiologic colleagues.

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Classification of idiopathic interstitial
pneumonia
KATZENSTEIN (1998) ATS/ERS (2002) Clinical diagnosis Pathologic Pattern
Usual interstitial pneumonia (UIP) Idiopathic pulmonary fibrosis (IPF) Usual interstitial pneumonia (UIP)
Desquamative interstitial pneumonia (DIP)/respiratory bronchiolitis interstitial lung disease (RBILD) Desquamative interstitial pneumonia (DIP)/respiratory bronchiolitis interstitial lung disease (RBILD) Desquamative interstitial pneumonia (DIP)/respiratory bronchiolitis interstitial lung disease (RBILD)
Acute interstitial pneumonia (AIP) Acute interstitial pneumonia (AIP) Diffuse alveolar damage (DAD)
Nonspecific interstitial pneumonia (NSIP) Nonspecific interstitial pneumonia (NSIP) Nonspecific interstitial pneumonia (NSIP
Cryptogenic organizing pneumonia (COP) Lymphoid interstitial pneumonia (LIP) Organizing pneumonia (OP) Lymphoid interstitial pneumonia (LIP)
American Thoracic Society/European
Respiratory Society
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Usual interstitial pneumonia (UIP)/ (idiopathic
pulmonary fibrosis)

• 60
• 6 7. decade (mean 59 year-old)
• Heterogeneus appearance (with alternating areas
  of normal lung, interstitial inflamation,
  fibrosis and honeycomb change)
• Subpleural parenchyma most severely affected
• Fibroblast foci
• Honeycomb chnage (cystically dilated bronchioles)

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Usual interstitial pneumonia (UIP) (idiopathic
pulmonary fibrosis)

• Fibrosis and fibrotic scar
• Mild interstitial inflamation
• Tip 2 pneumocyte hiperplasia
• Smooth muscle hyperplasia
• Osseous metaplasia
• Acute exacerbation (DAD or organizing pneumonia)
• Visscher DW, Myers JL. Proc Am Thorac Soc 2006
  3 322-329.

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Honeycomb change
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Fibroblast foci
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Desquamative interstitial pneumonia
(DIP)/respiratory bronchiolitis interstitial lung
disease (RBILD)

• Highly related and some indistinguishable
• DIP 8-17, RBIAH 2
• Mean 44 year-old
• Cigarette smoking
• DIP much more uniform, RBIAH patchy and
  bronchiolocentric distribution
• Pigmented alveolar macrophages, occasional
  multinucleated cells, eosinophils and lymphocytes
  within distal airspaces
• Inflamatory infiltrates and mild fibrosis in
  alveolar septa

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DIP
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RBILD
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Diffuse alveolar damage (DAD) / Acute
interstitial pneumonia (AIP)

• Mean 55 year-old
• Anologous ARDS, unknown etiology
• Late or organizing DAD
• Alveolar septa uniformly thickened, and distorted
  by proliferating fibroblast
• Hyperplasia o alveolar lining cells, remnants of
  hyaline membranes, fibrin thrombi
• Honeycomb change at 3 or 4 weeks

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DAD
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Nonspesific interstitial pneumonia (NSIP)

• 14-35
• Mean 48 year-old
• Idiopathic or connective tissue diseases,
  hipersensitivity pneumonia, drug-induced lung
  disease, chronic interstitial lung disease
  complicating DAD
• Inflamation and/or fibrosis - uniform
• Visscher DW, Myers JL. Proc Am Thorac Soc 2006
  3 322-329.

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NSIP

• Cellular NSIP Uniform alveolar septal infiltrate
  of mononuclear cells
• Fibrotic NSIP uniform collagen accumulation in
  alveolar septa, peribronchiolar interstitium,
  interlobular septa or visceral pleura

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Cellular NSIP
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Cellular and fibrotic NSIP
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Fibrotic NSIP
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Organizing pneumonia (OP) / Cryptogenic
organizing pneumonia (COP)

• Mean 55 year-old
• Patchy
• Polypoid plugs of loose organizing connective
  tissue in alveoli and/or bronchioli
• Mild interstitial inflamation
• Lung architecture is preserved.

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Lymphoid interstitial pneumonia (LIP)

• Very rare
• Mean 50 year-old
• Diffuse interstitial lymphoid infiltration
• Predominantly T lymphocyte, plasma cells and
  histiocytes
• Peribronchiolar lymphoid aggregates (B
  lymphocyte)

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Pathogenesis of UIP/IPF

• Inflammation (alveolitis) Hypothesis (1984)
• Neutrophil accumulation
• It is a consequence and not a cause of UIP/IPF
  (in advaced stage, due to the extensive tissue
  remodeling and traction bronchiectasis)
• Crystal RW. et al. N Engl J Med 1984 310
  235-244.
• Noble PW. et. al., Am J Respir Cell Mol Biol
  2005 33 113-120.

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Multiple hit hypothesis

• This hypothesis based on the idea that
  injury/inflammation of the alveolar-capillary
  constituents and basement membrane leads to type
  I epithelial and endothelial cells, the
  proliferation of type II cells, the loss of
  alveolar space integrity, the recruitment and
  proliferation of stromal cells and the deposition
  of the ECM.

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• The cycle of dysregulated repair involving an
  initial injury or inflammatory event is purported
  to lead to the perpetuation of chronic
  inflammation, with deposition of the ECM
  progressing inevitably to end-stage pulmonary
  fibrosis.
• Strieter RM. Chest 2005 128 526S-532S.
• Noble PW, Homer RJ. Clin Chest Med 2004 25
  749-758.
• White ES, et al. J Pathol 2003 201 343-354.

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Apoptosis and proliferation

• Tip II cells apoptosis and injury
• Pro-apoptotic protein (fas-fas ligand) and
  oxidative stress
• TNF ?
• TGF-?
• Angiotensin II

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Loss of basament membrane integrityFrustrated
epithelial cell generation
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Growth factors

• Keratinocyte growth factor (KGF),
• TGF-?,
• TGF-? ,
• Insulin-like growth factor-1 (ILGF-1),
• Platelet-derived growth factor (PDGF),
• Fibroblast growth factor-2
• Hepatocyte growth factor
• GF activate tyrosine kinase signaling pathways
• Fibroblast proliferation and matrix production
• Activation of wnt/? catenin signaling pathway

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Plasminogen activation system

• Critical to normal wound healing
• Plasminogen activated by tPA or uPA to plasmin
• Plasmin responsible for degrading fibrin clots
  and allowing for wound reepithelialization.
• Inhibits by plasminogen activator inhibitors
  (PAI).
• Overexpression of PAIs promotes fibrosis in IPF

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Angiogenesis and angiostasis

• Angiogenic activite
• Imbalance of pro-angiogenic chemokines (IL-8 ve
  ENA-78) and anti-angiogenic CXC chemokines
  (interstitial pneumonia-10-IP-10)
• VEGF
• Enhanced angiogenesis in earlier stage
• Loss of blood vessels in advanced stage

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Ekstracellular matrix production and degradation

• Imbalance of matrix production and degradation
• TGF-? promote matrix production and inhibit TIMP
  (Tissue inhibitor metalloproteinase)
• Degradation products inflammation and
  fibrosis
• Metalloproteinase could lead to basament membrane
  destruction

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Profibrotic Th2 cytokines

• IL-4, IL-5, IL-13
• The link between Th2 cytokines and fibrosis has
  been established in animal models.
• Directing therapies to restore the balance of Th1
  and Th2 cytokines is not an unreasonable approach

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Fibroblast and myofibroblast

• Origin resident cells ?, epithelial cells to
  transition to a mesenchymal phenotype ?
• IPF fibroblasts have different properties than
  normal lung fibroblast
• Bone marrow-derived precursors can contribute to
  the fibroblast pool after lung injury

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Myofibroblast

• In fibroblastic foci
• The production of new collagen and fibronectin
• Contractile properties
• (?SMA )
• In normal wound healing, appear transiently
• Normal fibroblasts differentiate into
  myofibroblasts in vivo ?

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Myofibroblast

• TGF ? induce the expression of ?SMA in normal
  lung fibroblasts
• TGF ? inhibits apoptosis of myofibroblast
• UIP myofibroblasts persist

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Abnormality in host defense

• The host factors that limit the extent of
  fibrosis
• Defects in endogeneus mechanism
• PG E2 have antifibrotic properties
• Fibroblasts from patients of IPF have been shown
  to have diminished capacity to produce PG E2
• Herpesvirus DNA is detected. Epithelial injury
  could occur in response to such viral infections.

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Summary

• IPF is a complex disorder
• Many pathogenic events have been observed
• Currently, no unifying hypothesis explains all
  the abnormalities
• The inciting event for lung injury is unknown
• Although more questions than answers currently
  exist, great strides are being made in
  elucidating new mechanisms in pathogenesis
• Future therapeutic approaches likely will target
  several pathways simultaneously with combinations
  of interventions

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Thank you