A hemorragia alveolar é uma síndrome que pode ocorrer como manifestação de uma série de doenças, cada uma com eventos fisiopatológicos diferentes resultando em sangramento pulmonar. A análise histológica detalhada destes pacientes pode auxiliar no entendimento desta síndrome. Neste estudo nós fizemos a revisão e descrição dos achados das lâminas de tecido pulmonar e do prontuário médico de 48 pacientes falecidos por hemorragia alveolar nos anos de 1999 a 2004. A maioria apresentou hemorragia de característica difusa (87,5%), predominantemente alveolar (79,2%), sem sinais de recorrência (79,2%) e com presença de fibrina (81,3%). As outras características avaliadas foram: vasculite (8,3%), trombose intravascular (27,1%),esclerose arterial (31,3%), capilarite (41,7%), acometimento intersticial (35,4%), acometimento venoso (41,7%), presença de sinais de infecção (50%), membrana hialina (25%). Com os registros médicos, classificamos os pacientes nas seguintes síndromes clínicas: congestão pulmonar (29,17%), coagulopatia (25%), sepse (27,08%) e inflamação (18,75%). Após as análises clínica e histológica, fizemos a correlação entre estes dados e encontramos que os pacientes com diagnóstico de congestão apresentaram menor presença de fibrina e de acometimento intersticial e maior presença de sangramento focal. O sangramento por coagulopatia se caracterizou por menor presença de fibrina e ausência de sinais de sangramento recorrente. Os pacientes com infecção clínica, histologicamente apresentaram fibrina e sinais de infecção no tecido pulmonar, já os pacientes com diagnóstico de inflamação se caracterizaram pela presença de fibrina, esclerose arterial e sangramento focal. Concluindo, nosso estudo sugere que alguns padrões histológicos são mais comuns em determinadas síndromes clínicas, e podem ser úteis no diagnóstico causal da hemorragia alveolar / Alveolar haemorrhage is a syndrome presented by many diseases each one with its particular physiopathologic mechanism resulting in pulmonary bleeding. The detailed histological analysis of these patients can help understanding this syndrome. In this study we reviewed and described histological findings of lung slides and medical records from patients whose cause of death was alveolar haemorrhage between 1999 and 2004. Most patients presented diffuse (87,5%), mainly alveolar (79,2%) rather than interstitial and recent bleeding with no signs of recurrence (79,2%). We also observed the presence of: fibrin (81,3%), vasculitis (8,3%), intravascular thrombosis (27,1%), arterial sclerosis (31,3%), capillarity (41,7%), interstitial involvement (35,4%), venous involvement (41,7%), signs of infection on lung tissue (50%) and hyaline membrane (25%). Clinically we classified the patients as having one of the following syndromes: pulmonary oedema due to congestive heart failure (CHF- 29,17%), coagulation disorders (25%), sepsis (27,08%) and systemic inflammation (18,75%). After correlating clinical and histological data we found CHF to have lower presence of fibrin and interstitial involvement and a greater presence of focal bleeding. Coagulation disorders were characterized by no signs of recurrent bleeding and a lower presence of fibrin than infection and inflammation. Patients with clinical diagnosis of systemic inflammation had a greater presence of fibrin and arterial sclerosis than other clinical syndrome and patients with clinical diagnosis of sepsis showed presence of signs of infection in lung tissue no matter the clinical site of infection. In conclusion, our study suggests that some histological patterns happens more commonly in determined clinical syndromes and can help diagnosing the cause of bleeding .

A hemorragia alveolar é uma síndrome que pode ocorrer como manifestação de uma série de doenças, cada uma com eventos fisiopatológicos diferentes resultando em sangramento pulmonar. A análise histológica detalhada destes pacientes pode auxiliar no entendimento desta síndrome. Neste estudo nós fizemos a revisão e descrição dos achados das lâminas de tecido pulmonar e do prontuário médico de 48 pacientes falecidos por hemorragia alveolar nos anos de 1999 a 2004. A maioria apresentou hemorragia de característica difusa (87,5%), predominantemente alveolar (79,2%), sem sinais de recorrência (79,2%) e com presença de fibrina (81,3%). As outras características avaliadas foram: vasculite (8,3%), trombose intravascular (27,1%),esclerose arterial (31,3%), capilarite (41,7%), acometimento intersticial (35,4%), acometimento venoso (41,7%), presença de sinais de infecção (50%), membrana hialina (25%). Com os registros médicos, classificamos os pacientes nas seguintes síndromes clínicas: congestão pulmonar (29,17%), coagulopatia (25%), sepse (27,08%) e inflamação (18,75%). Após as análises clínica e histológica, fizemos a correlação entre estes dados e encontramos que os pacientes com diagnóstico de congestão apresentaram menor presença de fibrina e de acometimento intersticial e maior presença de sangramento focal. O sangramento por coagulopatia se caracterizou por menor presença de fibrina e ausência de sinais de sangramento recorrente. Os pacientes com infecção clínica, histologicamente apresentaram fibrina e sinais de infecção no tecido pulmonar, já os pacientes com diagnóstico de inflamação se caracterizaram pela presença de fibrina, esclerose arterial e sangramento focal. Concluindo, nosso estudo sugere que alguns padrões histológicos são mais comuns em determinadas síndromes clínicas, e podem ser úteis no diagnóstico causal da hemorragia alveolar / Alveolar haemorrhage is a syndrome presented by many diseases each one with its particular physiopathologic mechanism resulting in pulmonary bleeding. The detailed histological analysis of these patients can help understanding this syndrome. In this study we reviewed and described histological findings of lung slides and medical records from patients whose cause of death was alveolar haemorrhage between 1999 and 2004. Most patients presented diffuse (87,5%), mainly alveolar (79,2%) rather than interstitial and recent bleeding with no signs of recurrence (79,2%). We also observed the presence of: fibrin (81,3%), vasculitis (8,3%), intravascular thrombosis (27,1%), arterial sclerosis (31,3%), capillarity (41,7%), interstitial involvement (35,4%), venous involvement (41,7%), signs of infection on lung tissue (50%) and hyaline membrane (25%). Clinically we classified the patients as having one of the following syndromes: pulmonary oedema due to congestive heart failure (CHF- 29,17%), coagulation disorders (25%), sepsis (27,08%) and systemic inflammation (18,75%). After correlating clinical and histological data we found CHF to have lower presence of fibrin and interstitial involvement and a greater presence of focal bleeding. Coagulation disorders were characterized by no signs of recurrent bleeding and a lower presence of fibrin than infection and inflammation. Patients with clinical diagnosis of systemic inflammation had a greater presence of fibrin and arterial sclerosis than other clinical syndrome and patients with clinical diagnosis of sepsis showed presence of signs of infection in lung tissue no matter the clinical site of infection. In conclusion, our study suggests that some histological patterns happens more commonly in determined clinical syndromes and can help diagnosing the cause of bleeding .

The context of this thesis is the modelling of particle deposition in the human lung in order to optimise the administration of inhaled drugs. As the alveolar region plays a crucial role both physiologically and functionally, especially for systemic delivery, the objective of this work is to set-up a particle deposition model specific to the acinar region which could be integrated in whole lung deposition model. The first two chapters concentrate on the anatomical and functional aspects of the lung and on the physical principles involved in the flow and particle transport mechanisms in the lung. Then a computational fluid dynamics model was setup in a simplified alveolar geometry. Aerosol bolus transport was studied through an Eulerian approach, for one or several breathing cycles. The impact of flow irreversibilities on bolus dispersion was quantified. The last chapter deals with the integration of the previous results in an analytical model of particle deposition in the whole lung. The results generated by this model are then compared to experimental data from the literature or obtained from an ongoing clinical trial. The results of the new theoretical model show an increase of particle deposition in the acinar region which improves correlation of theory with experimental data. This model could favourably help designing therapies targeting the alveolar region of the lung

<p>Akutni respiratorni distres sindrom (ARDS) predstavlja klinički sindrom koji se manifestuje te&scaron;kom respiratornom insuficijencijom sa razvojem akutnog edema pluća u odsustvu znakova popu&scaron;tanja leve polovine srca. S obzirom da ovaj sindrom ima heterogenu etiologiju, progresivan tok i visoku stopu mortaliteta, pravovremena i tačna dijagnoza esencijalna je u primeni efektivne i rane terapije, a samim tim i u pobolj&scaron;anju prognoze bolesti. Cilj ove doktorske disertacije bio je da se ispita povezanost kliničke i patohistolo&scaron;ke dijagnoze ovog sindroma, kao i da se analiziraju i uporede vrednosti kliničkih parametara neophodnih za postavljanje dijagnoze ARDS-a sa patohistolo&scaron;kim parametrima o&scaron;tećenja plućnog tkiva. Studija je obuhvatila 67 pacijenata Instituta za plućne bolesti Vojvodine koji su umrli pod kliničkom slikom ARDS-a i/ili kod kojih je na obdukciji patohistolo&scaron;ki dokazan ARDS. Za postavljanje kliničke dijagnoze ARDS-a kori&scaron;ćeni su kriterijumi The American-European Consensus Conference iz 1994. Nakon semikvantitativne analize patohistolo&scaron;kih parametara difuznog alveolarnog o&scaron;tećenja određivan je histolo&scaron;ki stadijum ARDS-a i svi pacijenti podeljeni su u dve grupe: I grupa - pacijenti u eksudativnoj fazi i II grupa - pacijenti u proliferativnoj fazi difuznog alveolarnog o&scaron;tećenja. Formirane grupe pacijenata upoređivane su u odnosu na vrednosti kliničkih parametara 12h pre smrtnog ishoda. U cilju procene prisustva komorbiditeta analizirani su indeks telesne mase (engl. body mass index- BMI) i podaci o prethodno dijagnostikovanoj arterijskoj hipertenziji. Kod svih pacijenata uključenih u studiju upoređivane su kliničke dijagnoze sa obdukcionim nalazom. Za klasifikaciju autopsijskih dijagnoza kori&scaron;ćena je Goldman-ova klasifikacija. Na osnovu provedenog istraživanja, do&scaron;lo se do zaključka da slaganje klinički dijagnostikovanih i patohistolo&scaron;ki potvrđenih slučajeva ARDS-a iznosi 68%. Senzitivnost kliničke dijagnoze ARDS-a iznosi 82%, a pozitivna prediktivna vrednost 80%. Pacijenti sa nalazom eksudativne faze DAD-a u plućnom tkivu su u najvećem procentu imali klinički težak ARDS, dok su se pacijenti sa nalazom proliferativne faze sindroma če&scaron;će manifestovali pod kliničkom slikom srednje te&scaron;kog ARDS-a, odnosno utvrđeno je da postoji statistička povezanost između nižih vrednosti PaO2/FiO2 i teže faze ARDSa. Patohistolo&scaron;kom analizom promena u plućnom tkivu nađeno je da najvažnija obeležja eksudativne faze ARDS-a predstavljaju: hijaline membrane, edem i krvarenje, dok su se kao najvažnija obeležja proliferativne faze ARDS-a izdvojili: proliferacija pneumocita tipa II, intersticijalna i mutilantna fibroza i organizirajuća pneumonija. Kod pacijenata sa kliničkom dijagnozom ARDS-a kod kojih ARDS nije i patohistolo&scaron;ki dokazan, najče&scaron;ći nalaz na plućima bila je fibrinozno-purulentna bronhopneumonija. Analizom etiolo&scaron;kih faktora koji doprinose razvoju ovog sindroma otkriveno je da je ARDS najče&scaron;će nastao kao posledica delovanja direktnih/pulmonalnih činilaca: pneumonije i virusa gripa H1N1. Najzastupljeniji komorbiditeti prisutni kod pacijenata sa ARDS-om bili su sistemska hipertenzija i gojaznost. Najzad, kod svih pacijenata uključenih u istraživanje upoređivane su kliničke dijagnoze sa obdukcionim nalazom i na osnovu Goldman-ove klasifikacije kliničke dijagnoze i obdukcioni nalaz slažu se u 72% slučajeva. Rezultati ove studije mogli bi se upotrebiti u daljim istraživanjima kako bi omogućili bolji dijagnostički pristup ovom problemu, a samim tim i bolji terapijski pristup i smanjivanje stope mortaliteta.</p> / <p>Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by severe respiratory failure with development of acute pulmonary edema in the absence of left heart failure signs. Since this syndrome has a heterogeneous etiology, progressive course and high mortality, timely and accurate diagnosis is essential in the implementation of effective and early treatment, and therefore in improving the prognosis of the disease. The aim of this PhD thesis was to examine the association between clinical and pathohistological diagnosis of this syndrome, as well as to analyze and compare the values of clinical parameters necessary for the diagnosis of ARDS with pathohistological parameters of diffuse alveolar damage. The study included 67 patients of the Institute for Lung Diseases who died under clinical picture of ARDS and / or in which, at the autopsy, pathohistological diagnosis of ARDS was set. To set up a clinical diagnosis of ARDS the criteria of the American-European Consensus Conference in 1994 were used. After a semi-quantitative analysis of histopathological parameters of diffuse alveolar damage, all patients were divided into two groups: Group I - patients in the exudative stage and Group II - patients in the proliferative phase of diffuse alveolar damage. Formed groups of patients were compared with respect to clinical parameters values 12 h before death. In order to assess the presence of comorbidities body mass index (BMI) and data on previously diagnosed arterial hypertension were analyzed. In all patients included in the study the clinical diagnosis were compared with autopsy findings according to Goldman&#39;s classification. According to this study, agreement of clinically diagnosed and histologically confirmed cases of ARDS is 68%. The sensitivity of clinical diagnosis of ARDS is 82%, and positive predictive value is 80%. Patients with exudative phase of DAD most frequently had a severe form of ARDS, whereas patients with proliferative phase often manifested with moderate form of ARDS, ie it was found that there is a statistical association between lower values PaO2 / FiO2 and more severe phase of ARDS. Pathological analysis of changes in lung tissue revealed that the most important characteristics of exudative phase of ARDS are: hyaline membrane, edema and bleeding, while the most important features of the proliferative phase of ARDS are: the proliferation of type II pneumocytes, interstitial fibrosis and mutilating and organizing pneumonia. In patients with a clinical diagnosis of ARDS in which ARDS was not pathohistologically proven, the most common finding in the lungs was fibrinous-purulent bronchopneumonia. The analysis of etiological factors that contribute to the development of this syndrome discovered that ARDS usually develop as a result of pulmonary factors: pneumonia and influenza virus H1N1. The most common comorbidities present in patients with ARDS were systemic hypertension and obesity. Finally, in all patients included in the study clinical diagnosis and autopsy findings were compared and based on Goldman&#39;s classification clinical diagnosis and autopsy findings are in agreement in 72% of cases. The results of this study could be used in further research to enable better diagnostic approach to this problem, and therefore a better therapeutic approach and reducing mortality rates.</p>

Mais de 60% dos pacientes com Doença Pulmonar Obstrutiva Crônica (DPOC) podem apresentar hiper-responsividade brônquica. Entretanto, não se sabe se, além das vias aéreas, o tecido pulmonar periférico também apresenta uma resposta exagerada a um agonista na DPOC. No presente estudo foi investigado o comportamento mecânico in vitro e as alterações estruturais e inflamatórias do tecido pulmonar periférico de 10 pacientes com DPOC comparados com 10 controles não fumantes. Foram realizadas medidas de resistência (R) e elastância (E) de fatias pulmonares em situação basal e após desafio com Acetilcolina. Também foram analisados no tecido alveolar as densidades de neutrófilos, eosinófilos, macrófagos, mastócitos e linfócitos CD8+ e CD4+, além do conteúdo de células positivas para -actina de músculo liso, fibras elásticas e colágenas. Os valores de R após o tratamento com Acetilcolina (RACh) e a porcentagem de aumento de resistência (%R) foram significativamente maiores no grupo DPOC comparado ao grupo controle (p0,03). O grupo DPOC também apresentou densidade de macrófagos (p=0,04) e linfócitos CD8+ (p=0,017) significativamente maior e conteúdo de fibras elásticas significativamente menor (p=0,003) comparado ao grupo controle. Foi observada uma correlação positiva significativa entre a %R e a densidade de eosinófilos e linfócitos CD8+ (r=0,608, p=0,002; e r=0,581, p=0,001, respectivamente), e também uma correlação negativa significativa entre a %R e a relação VEF1/ CVF (r=-0,451, p<0,05). Concluímos que a resposta colinérgica de fatias de parênquima pulmonar está aumentada em pacientes com doença pulmonar obstrutiva crônica e parece estar relacionada tanto à densidade de eosinófilos e de linfócitos CD8+ no tecido alveolar quanto ao grau de obstrução determinado pela prova de função pulmonar. / Up to 60% of COPD patients can present airway hyperresponsiveness. However, it is not known whether the peripheral lung tissue also presents an exaggerated response to agonists in COPD. In this study we investigated the in vitro mechanical behavior and structural and inflammatory changes of peripheral lung tissue of 10 COPD patients and compared to 10 non-smoking controls. We measured resistance (R) and elastance (E) of lung strips at baseline and after acetylcholine (ACh) challenge. We further assessed the alveolar tissue density of neutrophils, eosinophils, macrophages, mast cells and CD8+ and CD4+ cells, and the content of -smooth muscle actin+ cells, elastic fibers and collagen fibers. Values of R after ACh treatment (RACh) and percent increase of tissue resistance (%R) were significantly higher in COPD group compared to controls (p0.03). There was a significantly higher density of macrophages (p=0.04) and CD8+ cells (p=0.017) and a lower elastic fiber content (p=0.003) in COPD group compared to controls. We observed a significant positive correlation between %R and eosinophil and CD8+ cells density (r=0.608, p=0.002; and r=0.581, p=0.001, respectively), and also a negative correlation between %R and FEV1/FVC (r=-0.451, p<0.05). We conclude that the cholinergic responsiveness of parenchymal lung strips is increased in COPD patients and seems to be related to alveolar tissue eosinophilic and CD8 lymphocytic inflammation and also to the degree of airway obstruction at pulmonary function test.

Mais de 60% dos pacientes com Doença Pulmonar Obstrutiva Crônica (DPOC) podem apresentar hiper-responsividade brônquica. Entretanto, não se sabe se, além das vias aéreas, o tecido pulmonar periférico também apresenta uma resposta exagerada a um agonista na DPOC. No presente estudo foi investigado o comportamento mecânico in vitro e as alterações estruturais e inflamatórias do tecido pulmonar periférico de 10 pacientes com DPOC comparados com 10 controles não fumantes. Foram realizadas medidas de resistência (R) e elastância (E) de fatias pulmonares em situação basal e após desafio com Acetilcolina. Também foram analisados no tecido alveolar as densidades de neutrófilos, eosinófilos, macrófagos, mastócitos e linfócitos CD8+ e CD4+, além do conteúdo de células positivas para -actina de músculo liso, fibras elásticas e colágenas. Os valores de R após o tratamento com Acetilcolina (RACh) e a porcentagem de aumento de resistência (%R) foram significativamente maiores no grupo DPOC comparado ao grupo controle (p0,03). O grupo DPOC também apresentou densidade de macrófagos (p=0,04) e linfócitos CD8+ (p=0,017) significativamente maior e conteúdo de fibras elásticas significativamente menor (p=0,003) comparado ao grupo controle. Foi observada uma correlação positiva significativa entre a %R e a densidade de eosinófilos e linfócitos CD8+ (r=0,608, p=0,002; e r=0,581, p=0,001, respectivamente), e também uma correlação negativa significativa entre a %R e a relação VEF1/ CVF (r=-0,451, p<0,05). Concluímos que a resposta colinérgica de fatias de parênquima pulmonar está aumentada em pacientes com doença pulmonar obstrutiva crônica e parece estar relacionada tanto à densidade de eosinófilos e de linfócitos CD8+ no tecido alveolar quanto ao grau de obstrução determinado pela prova de função pulmonar. / Up to 60% of COPD patients can present airway hyperresponsiveness. However, it is not known whether the peripheral lung tissue also presents an exaggerated response to agonists in COPD. In this study we investigated the in vitro mechanical behavior and structural and inflammatory changes of peripheral lung tissue of 10 COPD patients and compared to 10 non-smoking controls. We measured resistance (R) and elastance (E) of lung strips at baseline and after acetylcholine (ACh) challenge. We further assessed the alveolar tissue density of neutrophils, eosinophils, macrophages, mast cells and CD8+ and CD4+ cells, and the content of -smooth muscle actin+ cells, elastic fibers and collagen fibers. Values of R after ACh treatment (RACh) and percent increase of tissue resistance (%R) were significantly higher in COPD group compared to controls (p0.03). There was a significantly higher density of macrophages (p=0.04) and CD8+ cells (p=0.017) and a lower elastic fiber content (p=0.003) in COPD group compared to controls. We observed a significant positive correlation between %R and eosinophil and CD8+ cells density (r=0.608, p=0.002; and r=0.581, p=0.001, respectively), and also a negative correlation between %R and FEV1/FVC (r=-0.451, p<0.05). We conclude that the cholinergic responsiveness of parenchymal lung strips is increased in COPD patients and seems to be related to alveolar tissue eosinophilic and CD8 lymphocytic inflammation and also to the degree of airway obstruction at pulmonary function test.