1. Restrictive lung diseases Acute and Chronic

2. Restrictive lung diseases (Diffuse Interstitial Lung Disease) A heterogeneous group of disorders characterized predominantly by diffuse and usually chronic involvement of the pulmonary connective tissue. Which level? – principally the most peripheral and delicate interstitium in the alveolar walls

3. Fibrosis Stiff lung

4. Restrictive lung diseases Characterized by reduced compliance of the lung. Caused by: – chest wall abnormalities Kyphoscoliosis sever obesity Guilian Barrre’ syndrome – parenchymal disease: Prominent changes in the interstitium (interstitial lung disease).  is an acute inflammatory demyelinating polyneuropathy, an autoimmune disease affecting the peripheral nervous system, usually triggered by an acute infectious process.autoimmuneperipheral nervous system  exhibits as an ascending paralysis noted by weakness in the legs that spreads to the upper limbs and the face along with complete loss of deep tendon reflexes.  With prompt treatment by plasmapheresis or intravenous immunoglobulins and supportive care, the majority of patients will regain full functional capacity.plasmapheresisimmunoglobulins

5. Restrictive lung diseases (Interstitial lung disease) Important signs and symptoms: -Dyspnea. -Hypoxia (caused by damage to the alveolar epithelium and interstitial vasculature produces abnormalities in the ventilation- perfusion ratio) - With progressive severe hypoxia, respiratory failure and cor pulmonale. - Chest radiographs show diffuse infiltration by small nodules, irregular lines, or "ground-glass shadows

6. Restrictive lung diseases (Interstitial lung disease) Can be: -Acute, edema in acute respiratory distress syndrome -Chronic, chronic inflammation and fibrosis.

7. ACUTE LUNG INJURY The term acute lung injury encompasses a spectrum of pulmonary lesions (endothelial and epithelial injuries) can be initiated by numerous conditions e.g. Aspiration of gastric contents and pneumonia

8. ACUTE LUNG INJURY Clinical Manifestations 1. acute onset of dyspnea 2. decreased arterial oxygen pressure (hypoxemia) 3. development of bilateral pulmonary infiltrates on radiographs 4. absence of clinical evidence of primary left-sided heart failure.

9. ACUTE LUNG INJURY The pulmonary infiltrates in acute lung injury are usually caused by damage to the alveolar capillary membrane ( different from left-sided heart failure) Result in noncardiogenic pulmonary edema.

10. ACUTE LUNG INJURY Acute lung injury can progress to the more severe acute respiratory distress syndrome

11. Acute Respiratory Distress Syndrome (ARDS)  ARDS is a clinical syndrome caused by diffuse alveolar damage (capillary and epithelial )  There is usually rapid onset of life-threatening respiratory insufficiency, cyanosis, and severe arterial hypoxemia that is refractory to oxygen therapy and that may progress to multisystem organ failure.  Clinical settings of ARDS:

12. Pathogenesis Direct Lung InjuryIndirect Lung Injury Common Causes PneumoniaSepsis Aspiration of gastric contentsSevere trauma with shock Uncommon Causes Pulmonary contusionCardiopulmonary bypass Fat embolismAcute pancreatitis Near-drowningDrug overdose Inhalational injuryTransfusion of blood products Reperfusion injury after lung transplantation Uremia

13. Progressive respiratory insufficiency caused by diffuse alveolar damage in the setting of sepsis, severe trauma, and diffuse pulmonary infections. Acute Respiratory Distress Syndrome (ARDS)

14. There is an imbalance of pro- and anti-inflammatory mediators causing acute inflammatory injury to the alveolar epithelium and capillary endothelium. Neutrophils and their products have a crucial role in the pathogenesis of ARDS. diffuse alveolar damage. Acute Respiratory Distress Syndrome (ARDS) Pathogenesis

15.  acute phase  organizing phase Acute Respiratory Distress Syndrome (ARDS) Morphology

16.  In the acute phase of ARDS the lungs are dark red, firm, airless, and heavy.  Microscopically, there is capillary congestion, necrosis of alveolar epithelial cells, interstitial and intra-alveolar edema and hemorrhage, and (particularly with sepsis) collections of neutrophils in capillaries. Acute Respiratory Distress Syndrome (ARDS) Morphology

17.  In the organizing stage there is marked proliferation of type II pneumocytes in an attempt to regenerate the alveolar lining.  Resolution is unusual Acute Respiratory Distress Syndrome (ARDS) Morphology

18.  organization of the fibrin exudates, with resultant intra- alveolar fibrosis.  Marked thickening of the alveolar septa ensues, caused by proliferation of interstitial cells and deposition of collagen.

19. Clinical Course  Approximately 85% of patients develop the clinical syndrome of acute lung injury or ARDS within 72 hours of the initiating insult.  The prognosis of ARDS is grim, and mortality rates have historically approached 100%.  Despite improvements in supportive therapy the mortality is still about 60%.  Predictors of poor prognosis in ARDS include : advanced age, underlying bacteremia (sepsis) the development of multisystem (especially cardiac, renal, or hepatic) failure.

20. Prognosis If the patient survive the acute stage, diffuse interstitial fibrosis may occur and continue to compromise respiratory function. However, in most patients who survive the acute insult and are spared the chronic sequela, normal respiratory function returns within 6 to 12 months.

21. SUMMARY  ARDS is a clinical syndrome of progressive respiratory insufficiency caused by diffuse alveolar damage  The setting are : sepsis, severe trauma, and diffuse pulmonary infections.  There is an imbalance of pro- and anti-inflammatory mediators causing acute inflammatory injury to the alveolar epithelium and capillary endothelium.  Neutrophils and their products have a crucial role in the pathogenesis of ARDS.  The characteristic histologic picture is that of alveolar edema, epithelial necrosis, accumulation of neutrophils, and presence of hyaline membranes lining the alveolar ducts.

22. RESPIRATORY DISTRESS SYNDROME OF THE NEWBORN  hyaline membrane disease  Pathogenesis RDS –is a disease of premature infants. –It occurs in about 60% of infants born at less than 28 weeks of gestation – Other contributing influences are maternal diabetes, cesarean section before the onset of labor, and twin gestation.

26. Chronic restrictive lung disease (Interstitial lung disease) Are a heterogenous group with little uniformity regarding terminology and classification. Many entities are of unknown cause and pathogenesis. Similar clinical signs, symptoms, radiographic alterations and pathophysiologic changes. Patient have reduced forced vital capacity, however the ratio is normal. Account for about 15% of non-infectious diseases.

27. Chronic restrictive lung disease Major Categories of Chronic Interstitial Lung Disease (CILD) -Fibrosing: Pneumoconiosis Usual interstitial pneumonia (idiopathic pulmonary fibrosis) Cryptogenic organizing pneumonia Associated with collagen vascular diseases Drug and Radiation Reactions -Granulomatous: Sarcoidosis Hypersensitivity pneumonitis. Wegener’s granulomatosis -Eosinophilic granuloma -Smoking related: Desquamative interstitial pneumonia Respiratory bronchiolitis-associated interstitial lung disease

28. CILD Idiopathic pulmonary fibrosis Hypersensitivity pneumonitis Smoking related Pneumoconiosis

29. Idiopathic pulmonary fibrosis Usual interstitial pneumonia Cryptogenic Organizing Pneumonia

30. Idiopathic pulmonary fibrosis (cryptogenic fibrosing alveolitis) (Usual interstitial pneumonia) UIP A clinicopathologic syndrome with characteristic radiologic, pathologic and clinical features. Characterized histologically by diffuse interstitial fibrosis and inflammation. Advanced cases result in sever hypoxemia and cyanosis. Males are more affected than female 2/3 of pt. older than 60 years

31. Pathogenesis Some form of alveolar wall injury result in interstitial edema and alveolitis. Type I pneumocyte is more susceptible to injury. Type II pneumocyte hyperplasia (regenerate). Fibroblast proliferation with progressive fibrosis of intra-alveolar exudate and interalveolar septa. IgG deposits are seen in alveolar wall. IL-8 leukotriens FGF, TGF- , PDGF

32. Morphology of IPF Gross - The lungs are firm. -Pulmonary edema. The morphologic changes vary according to the stage of the disease. Early cases: -Intraalveolar exudate. -Hyaline membranes. -Infiltration of the alveolar septa with mononuclear cells. -Hyperplasia of type II pneumocytes -

33. Morphology of IPF Advancing disease: - Organization of the intraalveolar exudates by fibrous tissue. -Thickening of the alveolar septa owing to fibrosis and variable amounts of inflammation. -Alternating areas of fibrosis and normal tissue. - Geographic variation - Temporal variation In the end, the lung consists of spaces lined by cuboidal or columnar epithelium separated by inflammatory fibrous tissue (honeycomb lung).

34. honeycomb lung

35. Clinical features of IPF Males are affected more often than females. Most patients are between 40 &70 years old. Gradual onset of dyspnea with respiratory difficulty. Hypoxemia and cyanosis. Cor pulmonale and cardiac failure may result. The progression in individual cases is unpredictable. The median survival is about 2 to 4 years.

36. Cryptogenic Organizing Pneumonia (COP) “brochiolitis obliterans organizing pneumonia” Pt. Present with cough and dyspensa with patchy areas of airspace consolidation radiographically. No interstitial fibrosis. Patient recover spontaneously or after oral steroids.

37. Cryptogenic Organizing Pneumonia

38. CILD Idiopathic pulmonary fibrosis Hypersensitivity pneumonitis Smoking related Pneumoconiosis

39. Desquamative interstitial pneumonia Smoking related Age : fourth decade Dyspnea and cough Complete recovery after cessation of smoking

40. CILD Idiopathic pulmonary fibrosis Hypersensitivity pneumonitis Smoking related Pneumoconiosis

41. Hypersensitivity pneumonitis An immunologically mediated inflammatory lung disease that primarily affects the alveoli and is therefore often called allergic alveolitis. Hypersensitivity to inhaled antigens in the form of organic such as moldy hay, e.g. farmer’s lung, humidified lung or pigeon breeder’s lung. May present either as an acute reaction with fever, cough, dypsnea and constitutional complains 4 to 8 hours after exposure or as a chronic disease with insidious onset of cough, dyspnea, malaise and weight loss.

42. Hypersensitivity pneumonitis Acute syndromes result from the combination of: -A direct irritant effect. -Activation of the alternate complement pathway. -Immune complex. The chronic form of the disease is mediated by delayed hypersensitivity reactions.

43. Selected cause of hypersensivity pneumonitis Syndrome Exposure Antigens ------------------------------------------------------------------------------------------------------------------------ Microbes contaminating vegetable matter of water. Farmer’s lung Moldy hay Micropolyspora faeni. Bagassosis Moldy pressed Thermophilic sugar cane Actinomycetes (bagasse) Maple bark disease Maple bark Cryptostroma Corticale Humidifier lung Cool-mist Thermophilic humidifier Actinomycetes Aureobasidium Animal products Pigeon breeder’s lungPigeons Pigeon serum proteins Chemicals Trimelitic anhydried Chemical industry Haptenated protein pneumonia

44. Morphology of hypersensitivity pneumonitis Mononuclear cell infiltrates in the alveoli and alveolar walls and around terminal bronchioles. Interstitial non- caseating granulomas reflecting type IV hypersensitivity reaction are present in more than two thirds of cases. Diffuse interstitial fibrosis in chronic exposure.

45. Morphology of hypersensitivity pneumonitis Clinical course is variable (stop antigen exopsure, pt. improve)

46. CILD Idiopathic pulmonary fibrosis Hypersensitivity pneumonitis Smoking related Pneumoconiosis

47. Non-neoplastic lung reaction to inhalation of mineral dusts. Most common dusts are coal dust, silica, asbestos and beryllium. Pathogenesis: The development of pneumoconiosis is dependent on: -The amount of dust retained in the lung and airways. a. Concentration of the dust in the ambient air. b. Duration of the exposure. c. Effectiveness of the clearance mechanisms. -The size (1-5  ) shape. -Their solubility and physiochemical activity. -The possible additional effects of other irritants, tobacco smoking. The particles are impacted at alveolar duct macrophage, accumulate inflammatory response fibrosis.

48. Pneumoconiosis Coal worker’s pneumoconiosis (CWP) Silicosis Asbestosis

49. Coal worker’s pneumoconiosis (CWP) Occurs in coal workers after many years of underground mine work. Two forms: -The simple form: - Focal aggregations of coal dust-laden macrophages (coal macules) mainly in upper lobes. - Patients have slight cough and blackish sputum. - emphysema ( smoking related). -The complicated form: With heavier pulmonary burdens of coal dust, fibrous scarring appears (complicated CWP) also callled progressive massive fibrosis (PMF).

50. Coal worker pneumoconiosis Morphology: Simple CWP: -Focal black pigmentations (macules), 1-2 mm up to 5 mm are scattered through the lung. -Mostly in the upper zones of the lower and upper lobes of the lungs. -Macules are composed of aggregations of coal dust-filled macrophages in close proximity to alveolar ducts.

51. Complicated CWP: - Black scars exceed 2 cm in diameter some times up to 10 cm -It consists of dense collagen and carbon pigments. -Cor pulmonale. -Miners who have rheumatoid arthritis and PMF are called Caplan’s syndrome. Coal worker pneumoconiosis Morphology:

52. Clinical course: –CWP is usually benign disease with little symptom –Minor cases progress to PMF –No increased risk to bronchogenic carcinoma Coal worker pneumoconiosis

53. Silicosis Long exposure to silica particles. Nodular densely fibrosing pneumoconiosis. Encountered in a diversity of industries: mining of gold, tin, copper and coal, sandblasting, metal grinding, ceramic manufacturing, drilling and tunneling. Pathogenesis: Crystalline silica is highly fibrogenic. Scattered lymphocytes and macrophages are drawn rapidly with fibrosis. Some particles are transported to lymph nodes.

54. Morphology of Silicosis Tiny collagenous nodules that enlarge forming stony-hard large fibrous scars usually in the upper lobes. The lung parenchyma between the scars may be compressed or emphysematous. Calcifications may appear (eggshell calcification). Similar collagenous nodules within the lymph nodes. Fibrous pleural plaques may develop.

55. Micro: -Hyalinized c ollagen fiber surround an amorphous center (fibrous nodules). - Scarring progress to PMF. -Scarring extending and encroching the pulmonary arteries. -Cor pulmonale. Morphology of Silicosis

56. depend on form of silicosis Clinical features of Silicosis

57. Forms of Silicosis Acute silicosis: –results from exposure to high dose of silica. Fluid in alveoli. – Pt. Have rapid onset of tachypnea, cough and repiratory failure. Chronic silicosis: –Inhalation of silica for long time with fibrotic nodules ( present in upper lobe of lung & in subpleural spaces Complicated silicosis: –Progression of chronic silicosis with PMF with chronic hypoxia Other pulmonary disease: –Increased susceptibility to TB –Caplan syndrome ( uncommon) –Lung cancer

58. Silica and lung cancer The relationship between silica and lung cancer has been a contentious issue, but in 1997, based on evidence from several epidemiologic studies, the International Agency for Research on Cancer concluded that crystalline silica from occupational sources is carcinogenic in humans. However, this subject continues to be controversial.

59. Asbestosis Asbestos is a family of crystalline hydrated silicates with a fibrous geometry. Two forms: –Serpentine chrysotile (flexible fiber), more common –Amphibole (straight and stiff fiber), more pathogenic Both forms are fibrogenic.

60. Asbestosis Inhalation of asbestos leads to: -Asbestos pneumoconiosis. -Pleural effusion. -Pleural adhesions. -Parietal pleural fibrocalcific plaques. -Increased incidence of mesothelioma, bronchogenic carcinoma, laryngeal cancer. These consequences occurs decades after exposure has ended. An increased incidence of asbestos-related cancers in family members of asbestos workers has alerted the general public to the potential hazards of asbestos in the environment.

61. Morphology Of Asbestosis diffuse pulmonary interstitial fibrosis scarring containing asbestos bodies.

62. Pleural plaque in asbestos Parietal pleura over dome of diaphragm

63. Asbestosis In asbestosis, pt. develop progressively worsened dyspnea with cough and sputum progressing to cor pulmonale and death. Both bronchogenic carcinoma and mesothelioma develop in workers exposed to asbestos. The risk of bronchogenic carcinoma is fivefold and for mesothelioma is 1000 fold greater. The risk of bronchogenic carcinoma in 50 X increased in smoking asbestos workers (but not that of mesothelioma)

64. Malignant Mesothelioma Rare cancer of mesothelial cells Arise from parietal or visceral pleura Can arise from peritoneum and pericardium 50% of pt. have history of exposure to asbestos at work It also appeared in relatives of asbestos worker or in people living near asbestos factory The latent period between exposure and malignant mesothelioma is long (25 to 40 years) Nearly all cases are related to amphibole asbestos These minerals cannot be removed from the lung and the risk for malignant mesothelioma is life long Simian virus 40 (SV40) T antigen is found in 60 to 80% of malignant mesothelioma Characteristic E/M finding : numerous long microvilli on cell surface

66. CILD Idiopathic pulmonary fibrosis Usual interstitial pneumonia Cryptogenic Organizing Pneumonia Pneumoconiosis Coal worker’s pneumoconiosis (CWP) Silicosis Asbestosis Hypersensitivity pneumonitis Desquamative interstitial pneumonia