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 . Interstitial lung disease. Interstitial inflamation and/or fibrosis 30% etiology + 70% idiopathic Open lung biopsy

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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

  • 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)

  • 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 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

Fibroblast foci

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



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


Nonspesific interstitial pneumonia (NSİP)

  • 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.


  • 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

Cellular and fibrotic NSIP

Fibrotic NSIP

Mean 55 year-old


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)

Very rare

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

  • 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

  • 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

Tip II cells apoptosis and injury

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

  • TNF 

  • TGF-

  • Angiotensin II

Loss of basament membrane integrityFrustrated epithelial cell generation

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

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

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

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

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

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

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 ?



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

  • TGF  inhibits apoptosis of myofibroblast

  • UIP myofibroblasts persist

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.


  • 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

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