Nonspecific Interstitial Pneumonia

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Nonspecific Interstitial Pneumonia

Disregulation of the Wnt pathway in human neoplasiaMutations of the APC ADENOMATOUS POLYPOSIS COLI gene• familial adenomatous polyposis• sporadic colon adenomas and carcinomasβ-CATENINLung metastasis ofColorectal carcinomaβ-CATENIN hyperexpressionand nuclear location


Bronchioles:β-catenin is normally expressed on thecell membranes


Alveoli:β-catenin accumulates in the nuclei ofproliferating type-II pneumocytes


Abnormal nuclear expression of β-Cateninat bronchiolo-alveolar junctions in UIP


p63CK5β-Cat Cyclin-D1 MMP7-Matrylisin


Proc Natl Acad Sci U S A 2002 Apr 30;99(9):6292-7Gene expression analysis reveals matrilysin as a keyregulator of pulmonary fibrosis in mice and humans.Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y,DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA.Pulmonary fibrosis is a progressive and largely untreatable group of disorders thataffects up to 100,000 people on any given day in the United States. To elucidate the molecularmechanisms that lead to end-stage human pulmonary fibrosis we analyzed samples frompatients with histologically proven pulmonary fibrosis (usual interstitial pneumonia) by usingoligonucleotide microarrays. Gene expression patterns clearly distinguished normal fromfibrotic lungs. Many of the genes that were significantly increased in fibrotic lungs encodedproteins associated with extracellular matrix formation and degradation and proteins expressedin smooth muscle. Using a combined set of scoring systems we determined thatmatrilysin (matrix metalloproteinase 7), a metalloprotease notpreviously associated with pulmonary fibrosis, was the most informative increasedgene in our data set. Immunohistochemisry demonstrated increased expression of matrilysinprotein in fibrotic lungs. Furthermore, matrilysin knockout mice were dramatically protectedfrom pulmonary fibrosis in response to intratracheal bleomycin. Our results identify matrilysinas a mediator of pulmonary fibrosis and a potential therapeutic target. They alsoillustrate the power of global gene expression analysis of human tissue samples to identifymolecular pathways involved in clinical disease.


Alveolar pneumocytesTA-p63P53p21waf1Proliferationand apoptosisΒ-catenincyclin-D1c-mycMatrilysin/MMP7∆N-p63P53p21waf1Bronchiolar basal cellsProliferationCell-motility - bronchiolization


UIP #01-220m-MEBronchiolization∆N-p63Alveolar cellsColumnar cellsBasal cells∆N-p63


Am J Pathol 1999 Oct;155(4):1033-8beta-catenin regulates the expression of thematrix metalloproteinase-7 in humancolorectal cancer.Brabletz T, Jung A, Dag S, Hlubek F, Kirchner T.Most colorectal cancers have loss of function mutations in the adenomatosispolyposis coli (APC) tumor suppressor gene. This leads to accumulation ofbeta-catenin, which together with the DNA binding protein TCF-4 functions as atranscriptional activator. Recently defined target genes are c-myc and cyclinD1, linking the APC gene defect to the capacity for autonomous proliferation ofcolon tumors. Here we report the identification of the matrix metalloproteinaseMMP-7 as another target gene of beta-catenin/TCF-4. MMP-7 is overexpressedin 80% of human colorectal cancers and known to be an important factor forearly tumor growth, with a potential function also for later progression steps,like invasion and metastasis. Our results explain the high percentageof MMP-7 overexpression in colon tumors. Moreover they indicatethat defects in the APC tumor suppressor gene may also have aninfluence on later steps of colon tumor progression.


Nuclearaccumulationof β-Catenin infibroblast fociof UIPB-catenin is accumulated in the nuclei ofmyofibroblast in Fibroblast Foci


Quale differenza traFibroblast-Foci eMasson’s body?β-CateninUIPCOP/BOOPB.S..#01-220L ME


COP/BOOPB.S..#01-220L ME• Plasma cells• Lymphocytes• neo-angiogenesis


Formation of Fibromyxoid Polypoid LesionsGranulation tissueTGF-βfibrinFibroblastproliferationFibroblast recruitmentand activation


Reversal of Fibromyxoid Polypoid LesionsApoptosisof fibroblastsMatrix MetalloproteinasesMacrophagephagocytosisApoptotic activity is increased in the newly formed fibromyxoid connectivetissue in bronchiolitis obliterans organizing pneumonia. Lappi-Blanco E, Soini Y,Paakko P. Lung 177:367,1999


BOOP: Degradazione dei polipi infiammatori intraalveolari:apoptosi e fagocitosiTenascin


Proc Natl Acad Sci U S A 2002 Apr 30;99(9):6292-7Gene expression analysis reveals matrilysin as a keyregulator of pulmonary fibrosis in mice and humans.Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y,DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA.Pulmonary fibrosis is a progressive and largely untreatable group of disorders thataffects up to 100,000 people on any given day in the United States. To elucidate the molecularmechanisms that lead to end-stage human pulmonary fibrosis we analyzed samples frompatients with histologically proven pulmonary fibrosis (usual interstitial pneumonia) by usingoligonucleotide microarrays. Gene expression patterns clearly distinguished normal fromfibrotic lungs. Many of the genes that were significantly increased in fibrotic lungs encodedproteins associated with extracellular matrix formation and degradation and proteins expressedin smooth muscle. Using a combined set of scoring systems we determined thatmatrilysin (matrix metalloproteinase 7), a metalloprotease not previously associatedwith pulmonary fibrosis, was the most informative increased gene in our data set.Immunohistochemisry demonstrated increased expression of matrilysin protein in fibroticlungs. Furthermore, matrilysin knockout mice were dramatically protected from pulmonaryfibrosis in response to intratracheal bleomycin. Our results identify matrilysin as a mediator ofpulmonary fibrosis and a potential therapeutic target. They also illustrate the power ofglobal gene expression analysis of human tissue samples to identify molecular pathwaysinvolved in clinical disease.


CK5


Smooth muscleproliferationBronchiole


Injury at bronchiolo-alveolar junctionsproliferationBronchiolar epitheliumWnt-activationField-EffectapoptosisAlveolar epithelium


Perche’ aspettare lelucerne?Breve e’ il tempo.O amato fanciullo, prendile grandi tazzevariopinte,perche’ il figliodi Zeus e di Semelediede agli uomini il vinoper dimenticare i dolori.Alceo


Nuclear accumulation of beta-catenin inbronchiolar lesions and fibroblast foci in Idiopathicpulmonary fibrosis: A possible clue of abnormalWnt-pathway activationMarco Chilosi, Venerino Poletti, Alberto Zamò, Maurizio Lestani, LiciaMontagna, Paola Piccoli, Serena Pedron, Manuela Bertaso, Aldo Scarpa,Barbareschi Mattia, Bruno Murer, Gianpietro Semenzato, and ClaudioDoglioniSubmitted 2002


Can be the wnt-pathwayfarmacologically manipulated?


Clin Cancer Res 2002 Mar;8(3):893-903Resveratrol induces growth inhibition, S-phasearrest, apoptosis, and changes in biomarkerexpression in several human cancer cell lines.Joe AK, Liu H, Suzui M, Vural ME, Xiao D, Weinstein IB.…. In SW480 cells, cyclin A, cyclin B1, and beta-cateninexpression levels were decreased within 24 h. There was adecrease in cyclin D1 expression after only 2 h of treatment, andthis persisted for up to 48 h. ……..CONCLUSIONS: These studies provide support for the use ofresveratrol in chemoprevention and cancer therapytrials. Cyclin D1, cyclin B1, beta-catenin, and apoptoticindex could be useful biomarkers to evaluate treatmentefficacy.


Am J Respir Crit Care Med 2002 Jan 15;165(2):277-304American Thoracic Society/European Respiratory Society International MultidisciplinaryConsensus Classification of the Idiopathic Interstitial Pneumonias.


2002 IIP entities(in order of frequency)Idiopathic Pulmonary Fibrosis (IPF/UIP)Nonspecific Interstitial Pneumonia (NSIP)Cryptogenic organizing Pneumonia (COP/BOOP)Acute Interstitial Pneumonia (AIP/DAD)Respiratory Bronchiolitis-associated (RB-ILD)Desquamative Interstitial Pneumonia (DIP)Lymphoid Interstitial Pneumonia (LIP)Am J Respir Crit Care Med 2002 Jan 15;165(2):277-304American Thoracic Society/European Respiratory Society International MultidisciplinaryConsensus Classification of the Idiopathic Interstitial Pneumonias.


The new classification defines a set ofHistologic Patternsthat provide the basis for a final clinico-radiologicpathologicdiagnosisUsual Interstitial Pneumonia (UIP/IPF)Nonspecific Interstitial Pneumonia (NSIP)Diffuse Alveolar Damage (DAD/AIP)Respiratory Bronchiolitis (RBILD)Desquamative Interstitial Pneumonia (DIP)Organizing Pneumonia (BOOP/COP)Lymphoid Interstitial Pneumonia (LIP)Am J Respir Crit Care Med 2002 Jan 15;165(2):277-304American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classificationof the Idiopathic Interstitial Pneumonias.


Achieving a correct diagnosis is adynamic process. The final diagnosis should be renderedonly after the pulmonologist, radiologist,and pathologist have reviewed all the data.Am J Respir Crit Care Med 2002 Jan 15;165(2):277-304American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classificationof the Idiopathic Interstitial Pneumonias.


Interstitial Fibrosispathogenesis Injury Tissue Damage Inflammation Repair Remodeling Fibrosis


Interstitial lung diseasespathogenesis sarcoidosis DIP NSIP DAD Hypersinsitivity pneumonitis (AEA) drug hypersensitivityEarly interstitial inflammationalveolitis


Polmonite interstizialeCD3 linfociti TMacrofagi alveolari


Cytokeratin 8-18


Pulmonary Fibrosis: PathogenesisAm J Respir Crit Care Med 1999 Nov;160(5 Pt 1):1771-7 NHLBI Workshop Summary. Pharmacological therapy foridiopathic pulmonary fibrosis. Past, present, and future. Mason RJ, Schwarz MI, Hunninghake GW, Musson RA.


Interstitial Fibrosispathogenesis Acute Interstitial Pneumonia (DAD) Organizing Pneumonia Nonspecific Interstitial Pneumonia


Acute Interstitial Pneumonia (AIP)ARDS IDIOPATICODanno acuto, diffuso,coinvolgente ampie regioni diparenchima alveolare


Reazione al danno acuto del parenchima polmonareStimolazione dei macrofagi alveolariProduzione di IL-8, Chemiotassie stimolazione dei PMNDanno al sistema capillareinondazione degli alveoliSecrezionedi elastasi e MPXAlveoloSP-AIL-8MembraneialineTTF1Danno e necrosi alveolarecon proliferazionecompensativa deipneumociti II


Acute Interstitial Pneumonia (AIP)ARDS IDIOPATICOCaratteristiche istopatologiche del danno alveolarediffuso (DAD):• fase essudativa• fase proliferativa• fase fibrosanteEdema, flogosi interstiziale, membrane ialine,iperplasia pneumociti II (con cellule atipiche),miofibroblasti interstiziali, tessuto di granulazioneintra-alveolare


CK8α-SMA• Danno e necrosi dell’epitelio alveolare (+endotelio)• Attivazione del processo riparativo• Proliferazione di pneumociti IIReazione al danno delparenchimapolmonare• Proliferazione di fibroblasti e miofibroblasti


Am J Pathol 1996 Aug;149(2):531-8Association of p53 and WAF1 expressionwith apoptosis in diffuse alveolar damage.Guinee D Jr, Fleming M, Hayashi T, Woodward M, Zhang J, Walls J, Koss M,Ferrans V, Travis W.Little is known about alterations in cell cycle regulatory proteins such as p53and WAF1 in diffuse alveolar damage (DAD). We hypothesized that up-regulationof p53 and WAF1 in type II pneumocytes in DAD is associated with underlyingDNA damage and apoptosis. Twenty cases of DAD and twenty control specimens oflung adjacent to resected tumors were studied. Immunohistochemical stains withantibodies recognizing p53 and WAF1 were performed, and apoptosis was assessedin sixteen cases by the nick end-labeling method. We identified p53 expression andapoptosis in all cases of DAD but not in any of the control lungs. We detectedWAF1 expression in nineteen of twenty cases of DAD and in sixteen of twentycontrol lungs. In general, the distribution and intensity of WAF1 staining weregreater in DAD than in control lungs. Staining for both p53 and WAF1 and labelingof apoptotic cells in DAD were usually focal ( < 10% of cells) and predominantlylocalized in type II pneumocytes. We conclude that increased p53 and WAF1expression in DAD reflects normal physiological up-regulation in response tocellular and DNA damage and is associated with apoptosis of type II pneumocytes.p53-dependent apoptosis may contribute to the pathogenesis of this disease.


EPITHELIAL INJURYFREE RADICALSSuperoxide O 2-y H 2O 2y OH -y O 2.DNA Damagep53Apoptosisbcl-2Baxp21 waf1Cell-cycle blockp53p21


• Usual Interstitial Pneumonia (UIP/IPF)• Acute Interstitial Pneumonia (AIP)• Desquamative Interstitial Pneumonia (DIP)• Respiratory Bronchiolitis Interstitial Lung Disease (RBILD)• Nonspecific Interstitial Pneumonia (NSIP)• Idiopathic BOOP/COP• Lymphocytic Interstitial Pneumonia (LIP)


Organizing Pneumonia (OP/COP/BOOP) Reazione non specifica, riparativa,osservabile comunemente in vari tipidi patologie diffuse o localizzate inseguito a danno acuto o subacuto. Il danno coinvolge discrete regionidi parenchima alveolare eperibronchiolare


COP/BOOPB.S..#01-220C ME


Danno al parenchima alveolareRiparazione: Polipi infiammatori, corpi di MassonBronchiolitis Obliterans OrganizingPneumonia (OP/BOOP)Tenascinα-SMA


BOOP/COP Caratteristiche istopatologiche del danno• danno acuto/subacuto• necrosi alveolare discreta e/o migrante• fase proliferativa alveolare• fase di organizzazione intraluminale• collasso alveolare ed organizzazioneEdema, flogosi alveolare,iperplasia pneumociti II,tessuto di granulazione intraalveolare(polipi infiammatori) chesi estendono al bronchiolo.Tenascin


• Usual Interstitial Pneumonia (UIP/IPF)• Nonspecific Interstitial Pneumonia (NSIP)•Acute Interstitial Pneumonia (AIP)•Respiratory Bronchiolitis Interstitial Lung Disease (RBILD)•Idiopathic BOOP/COP•Desquamative Interstitial Pneumonia (DIP)• Lymphocytic Interstitial Pneumonia (LIP)


Nonspecific Interstitial PneumoniaNSIP• Cellular pattern• Mixed pattern• Fibrosing patternTemporal uniformity, diffuse inflammatory infiltration,thickening of interstiatial spaces, variable fibrosing processKatzenstein and Fiorelli: Nonspecific interstitial pneumonia/fibrosis: histologicpatterns and clinical significance. Am J Surg Pathol 1994; 18:136-147


Nonspecific Interstitial PneumoniaNSIPCellular patternMixed patternFibrosing patternNSIP should be separated into cellular and fibrosingpatterns, because these histologic patterns are associatedwith different clinical characteristics and prognoses.Travis WD et al. : Idiopathic nonspecific interstitial pneumonia:prognostic significance of cellular and fibrosing patterns.Survival comparison with UIP and DIP. Am J Surg Pathol 2000;24:19-33


NSIPcellular patternTenascin


NSIPfibrosingpatternTenascinCK8


NSIPDIP +NSIP cellularpatternNSIPfibrosing patternUIPTravis WD et al. : Idiopathic nonspecific interstitial pneumonia: prognosticsignificance of cellular and fibrosing patterns. Survival comparison with UIP and DIP.Am J Surg Pathol 2000; 24:19-33

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