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NEW INSIGHTS INTO PATHOGENESIS OF UIP/NSIP. Dr. Derya Gumurdulu Cukurova University, Faculty of Medicine, Department of Pathology, Adana . Interstitial lung disease. Interstitial inflamation and/or fibrosis 30% etiology + 70% idiopathic Open lung biopsy

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New insights into pathogenesis of uip nsip

NEW INSIGHTS INTO PATHOGENESIS OF UIP/NSIP

Dr. Derya Gumurdulu

Cukurova University, Faculty of Medicine, Department of Pathology, Adana


Interstitial lung disease
Interstitial lung disease

  • Interstitial inflamation and/or fibrosis

  • 30% etiology +

  • 70% idiopathic

  • Open lung biopsy

  • Communication between the pathologist and clinical and radiologic colleagues.


Classification of idiopathic interstitial pneumonia

*: American Thoracic Society/European Respiratory Society


Usual interstitial pneumonia uip idiopathic pulmonary fibrosis
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)


Usual interstitial pneumonia uip idiopathic pulmonary fibrosis1
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.


Honeycomb change fibrosis)


Fibroblast foci fibrosis)


Desquamative interstitial pneumonia dip respiratory bronchiolitis interstitial lung disease rbild
Desquamative interstitial pneumonia (DIP)/respiratory bronchiolitis interstitial lung disease (RBILD)

  • Highly related and some indistinguishable

  • DIP 8-17%, RBİAH 2%

  • Mean 44 year-old

  • Cigarette smoking

  • DİP much more uniform, RBİAH patchy and bronchiolocentric distribution

  • Pigmented alveolar macrophages, occasional multinucleated cells, eosinophils and lymphocytes within distal airspaces

  • İnflamatory infiltrates and mild fibrosis in alveolar septa


DIP bronchiolitis interstitial lung disease (RBILD)


RBILD bronchiolitis interstitial lung disease (RBILD)


Diffuse alveolar damage dad acute interstitial pneumonia aip
Diffuse alveolar damage (DAD) / bronchiolitis interstitial lung disease (RBILD)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


DAD bronchiolitis interstitial lung disease (RBILD)


Nonspesific interstitial pneumonia ns p
Nonspesific interstitial pneumonia (NSİP) bronchiolitis interstitial lung disease (RBILD)

  • 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.


NSIP bronchiolitis interstitial lung disease (RBILD)

  • Cellular NSIP: Uniform alveolar septal infiltrate of mononuclear cells

  • Fibrotic NSIP: uniform collagen accumulation in alveolar septa, peribronchiolar interstitium, interlobular septa or visceral pleura


Cellular NSIP bronchiolitis interstitial lung disease (RBILD)


Cellular and fibrotic NSIP bronchiolitis interstitial lung disease (RBILD)


Fibrotic NSIP bronchiolitis interstitial lung disease (RBILD)


Organizing pneumonia op cryptogenic organizing pneumonia cop

Mean 55 year-old bronchiolitis interstitial lung disease (RBILD)

Patchy

Polypoid plugs of loose organizing connective tissue in alveoli and/or bronchioli

Mild interstitial inflamation

Lung architecture is preserved.

Organizing pneumonia (OP) / Cryptogenic organizing pneumonia (COP)


Lymphoid interstitial pneumonia lip

Very rare bronchiolitis interstitial lung disease (RBILD)

Mean 50 year-old

Diffuse interstitial lymphoid infiltration

Predominantly T lymphocyte, plasma cells and histiocytes

Peribronchiolar lymphoid aggregates (B lymphocyte)

Lymphoid interstitial pneumonia (LIP)


Pathogenesis of uip ipf
Pathogenesis of UIP/IPF bronchiolitis interstitial lung disease (RBILD)

  • 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.


Multiple hit hypothesis
Multiple hit hypothesis bronchiolitis interstitial lung disease (RBILD)

  • 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.


  • 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.


Apoptosis and proliferation
Apoptosis and proliferation 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.

Tip II cells apoptosis and injury

  • Pro-apoptotic protein (fas-fas ligand) and oxidative stress

  • TNF 

  • TGF-

  • Angiotensin II


Loss of basament membrane integrity frustrated epithelial cell generation
Loss of basament membrane integrity 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. Frustrated epithelial cell generation


Growth factors
Growth factors 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.

  • 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


Plasminogen activation system
Plasminogen activation system 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.

  • 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


Angiogenesis and angiostasis
Angiogenesis and angiostasis 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.

  • 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


Ekstracellular matrix production and degradation
Ekstracellular matrix production and degradation 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.

  • 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


Profibrotic th2 cytokines
Profibrotic Th2 cytokines 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.

  • 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


Fibroblast and myofibroblast
Fibroblast and myofibroblast 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.

  • 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


Myofibroblast

In fibroblastic foci 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.

The production of new collagen and fibronectin

Contractile properties

(SMA +)

In normal wound healing, appear transiently

Normal fibroblasts differentiate into myofibroblasts in vivo ?

Myofibroblast


Myofibroblast1
Myofibroblast 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.

  • TGF  induce the expression of SMA in normal lung fibroblasts

  • TGF  inhibits apoptosis of myofibroblast

  • UIP myofibroblasts persist


Abnormality in host defense
Abnormality in host defense 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.

  • 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.


Summary
Summary 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.

  • 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


Thank you 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.


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