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Aim The aim of this practical class is to examine the pathogenesis of chronic lung disease caused by environmental factors, and to correlate the microscopic and macroscopic appearances of pulmonary lesions with their clinical manifestations. Learning objectives At the completion of this practical class you should be able to:

  1. Discuss the pathogenesis of important forms of chronic pulmonary disease.
  2. Describe the microscopic appearance of pulmonary lesions and correlate this with their clinical manifestations.
  3. Interpret various tests of pulmonary function.
  4. Discuss the prognosis and complications of pulmonary disease.
  5. Outline the pathophysiology of interstitial pneumonitis.

Station 1

Case 1 - Clinical History

A 42 year old man who had a long history of intermittent dyspnoea associated with expiratory wheezing and chest tightness presented to the emergency room of his local hospital. He had developed a cold 3 days earlier and during the night had become very short of breath. His regular medications did not seem to have any effect. The man had never smoked. On examination, his respiratory rate was 30/min and widespread wheezing was audible in both lung fields. The following results of investigations were obtained:

Task 1 How would you interpret the above results? What is your provisional diagnosis?

  • DDx asthma
    • Spirometry = obstructive disease
  • Low pO2, and O2 saturation
  • Intermittent episodes of dyspnoea – hallmark of asthma
  • Cold (rhinovirus esp serogroup C) → triggers asthma – acute exacerbation of asthma – viral infections is no.1 exacerbater of asthma namely Rhinovirus
    • Means normal therapy will no longer work (because it has exacerbated)
    • Rhinovirus A, B and C
  • pCO2 is normal and pO2 is low
    • Obstructive → fall in pO2
      • Due to mucus obstruction NOT bronchospasm
    • Low pO2 → hyperventilation is normal response → blow off pCO2 (CO2 is much more diffusible than O2 is)
    • Now that pCO2 is normal means that this is very severe because he can no longer blow off anymore pCO2
      • So this person is in respiratory failure
    • Pure obstructive because his FVC is normal

Task 2 The man was commenced on salbutamol, a β2 adrenergic agonist, by nebuliser and given an intravenous dose of hydrocortisone, a corticosteroid. Given your knowledge of the pathogenesis of this disease, what is the intended action of these drugs?

  • Hydrocortisone
    • Long-acting
      • Anti-inflammatory
  • Normal medication
    • Anti-inflammatories – glucocorticoids
      • Inhalation – local action – low dosage – no systemic effects
      • In an exacerbation this therapy no longer works, DOES NOT mean that drugs no longer works
      • Means that this method of delivery no longer works
      • Mucus plug will influence drug administration
      • Obviously can no longer inhale as well
      • Deliver systemically may be better → hence higher dose is required
  • Eosinophilic vs neutrophilic infiltration with asthma – still undecided
  • People who get really sick from exacerbation – glucocorticoid resistant
    • Generally steroids are very effective in suppressing eosinophil recruitment
    • Not effective on neutrophil recruitment
  • Inflammation is the critical event in the acute exacerbation. Not well understood how virus triggers exacerbation. Inflammatory response to a viral infection triggers a stronger allergic response that is mixed. Treatment with steroids (good for allergic) is not as good with the exacerbation
    • Airway obstruction in acute exacerbation is mainly oedema (not just mucus and bronchospasm)
      • Therefore the acute exacerbation management is imperfect - some people die of asthma still

The man did not respond to these medications and was transferred to the Intensive Care Unit. He died several hours later in respiratory failure. Virtual slide 1 and specimen 1872.9 were prepared from tissues removed at autopsy. Task 3 - see the Phase 1 version of this

  • Briefly note the features of the macroscopic specimen and virtual slide 1 that are consistent with your understanding of this disease process.
  • NB this picture is of a person who died WITH asthma NOT BECAUSE of asthma (but if you see the slideshow, you can see someone who died OF asthma - oedematous wall, epithelial sloughing, and mucus plugging)
    • Vslides = moderate asthma, stable
  • Full thickeness violent inflammation
  • Every blood vessel is dilated
  • Inflammatory cells everywhere (in mucous, epithelium etc)
  • Widespread Epithelial loss and shedding
  • Proteolytic enzymes released → breakdown of intrapethlial junctions
  • Presence of Goblet cells (hyperplasia and metaplasia)
  • Mucus
  • Subepithelial fibrosis – band of collagen (pink line)
  • Presence of eosinophils intraepithelially & lymphocytes
  • Mucus plugging and collapse of the airways (plugging not visible on slide, epithelium not sloughed)
  • Mast cells that can be seen via immunostaining
    • Inspissated mucus = dries out mucus. Hyperventilation = dead space ventilation, dries out the mucus (an example of insensible perspiration). Exercise-induced asthma (in cold, dry air), the dehydration is the mechanism: affects mucosa and the mucus = making more mucus AND it's getting dehydrated = cork in airways. Therefore management of asthma includes physiotherapy. Mucolytics also include steambaths and N-acetylcysteine.
  • Slight smooth muscle hypertrophy
  • Reason for alveola collapse
    • Obstructed lumen to the airways → resorption of the gases

Resorption collapse

    • Other form of collapse → compression collapse – external pressure e.g. pleural effusion


  • Inflammation in the airway wall
  • Epithelial damage
  • Smooth muscle hyperplasia
  • Reversible airflow obstruction
  • Bronchial hyperreactivity


  • Childhood asthma – typically allergic/eosinophillic
    • Genetics – atopy
    • Early-life respiratory viral infections vs other early life exposure to pathogens/microbial products
    • Recurrent exposure to allergens
    • Early/recurrent exposure to environmental irritants
  • Adult-onset asthma – may be non-allergic/neutrophilic
    • Occupational exposures
    • Aspirin sensitivity


OLD CASE: A 55 year old man complained of worsening breathlessness for over 12 months. He now had difficulty climbing the stairs in his house. On further questioning, he had also had a non-productive cough for most of this period. He was a lifelong non-smoker.

The following investigative results were obtained:

Task 4 How would you interpret the results of these investigations? What further investigations might be required to establish a diagnosis in this case?

  • DDx
    • Coal miner: Pulmonary fibrosis → silicosis
    • Our variation: of this question had no coal mining history: idiopathic pulmonary fibrosis secondary to interstitial lung disease
  • CXR: reticular fibrosis, diffuse = chronic interstitial lung disease
  • Restricted Pattern:
    • Elevated FEV1/FVC (N.B. ratio only confirms a obstructive diagnosis not restrictive)
    • Decreased FVC and Decreased FEV¬1
  • Further Investigations
    • CT
    • Open-Lung Biopsy if no occupational history
    • LFTs, UEC, Creatinine etc. → check normal function
    • Blood gases

The man’s lung function progressively deteriorated, and he died several years later in respiratory failure. Virtual slide 2 and specimen 2522.9 were prepared from tissue removed at autopsy.

Task 5 Examine virtual slide 2 and specimen 2522.9, which show changes consistent with silicosis. What abnormalities are present? How might inhalation of silica have led to these changes? Coal miner

  • No more fibroblasts = Nodules with no nuclei
  • Pink + collagen + no more fibroblasts = hyaline cartilage
    • Have undergone remodelling
  • Black deposits generally occur around periphery → picked up by macrophages → generally not harmful
  • Presence of lots of lymphocytes
  • Some inflammation around the outside
  • Large nodules → necrosis in the centre more commonly
    • >5cm can capitate in the middle
      • Secondary infection can occur

Our variant:

  • Chronic interstitial lung disease
  • Histo:interstitial and/or intra-alveolar deposition of collagen with irregular collapse and irreversible reorganisation of airspace architecture, following parenchymal inflammation
  • wikipedia:Idiopathic pulmonary fibrosis secondary to chronic wikipedia:Interstitial lung disease
  • CXR: widespread opacification due to pulmonary fibrosis
  • Radiological features
    • The CT imaging findings complements the histology. It is more correct to describe characteristic imaging pattern as UIP rather than IPF, a terminology assigned for the idiopathic clinical syndrome of UIP.
    • Alveoli collapse down, increased air spaces, overall airspaces that are nonfunctional images
    • A UIP-pattern of fibrosis is characterised by honeycombing cysts and reticular septal thickening with subpleural and posterior basal predominance. Traction bronchiectasis can also be observed, however, this is a general feature of fibrosis not specific to UIP-pattern .In a subgroup of patients the imaging finding of UIP overlap with NSIP and biopsy may be necessary to obtained the correct diagnosis.
    • Groundglass appearance
    • Radiological:
    • CT scan in the lecture is not specific to hypersensitivity pneumonitis - it's common to all interstitial lung disease
  • Macro: honeycomb change = scarred bits and big air-trapping bits. Very course honeycomb structure.
    • Asterixes show bits of lung that aren't too bad - just congested
  • Don't know why the lower part is more affected while the upper part is spared
  • Consequence: pulmonary arteriolar hypertension - increase in the thickness of arteriolar walls because of increase load on the right heart - cor pulmonale
  • Bronchiolitis obliterans with organising pneumonia - starts off with granulation tissue on the distal airways
  • High Res CT is the most useful diagnostic tool
  • Looking for organisms, people may do bronchoalveolar lavage
    • Then they go for a lung biopsy to make sure it is idiopathic
      • e.g. undiagnosed TB, undiagnosed fungal infections or unexpected occupational exposures
      • mostly biopsies just show extensive fibrosis
  • Restrictive spirometry; decreased compliance
  • Nonproductive cough due to ongoing lower airway inflammation
  • [NB: Carbon in perivascular lymph bundles because scarring prevents drainage]


Case History A 68 year old man developed increasing dyspnoea over 10 years. He had suffered from a chronic cough for "many years", and had smoked 40 cigarettes/day for the past 50 years. There was a past history of pneumonia 3 years previously and recurrent episodes of "bronchitis" over the past 20 years. Examination revealed a thin man, dyspnoeic at rest with prolonged expiration, using his accessory respiratory muscles. On auscultation of the chest, there were bilateral expiratory rhonchi. His cough was productive of copious mucopurulent sputum.

Task 6 What is the most likely cause of this man's symptoms? How would you substantiate your provisional diagnosis?

  • COPD: emphysema + chronic bronchitis
    • Prolonged expiration: increased lung compliance → hyperinflation → hard to expirate
    • Dyspnoea: new air not being exchanged (old air remains as can not remove it)
      • Went over a few years
    • Chronic cough: build up of mucous + irritation
    • Pneumonia: mucociliary escalator impaired → increased susceptibility to infection
    • Infection could have exacerbated COPD
    • Smoking is a risk factor
  • PaO2 = low + PaCO2 = normal
    • NB: if PaCO2went high, bicarb rises and pH falls = SEVERE + bad ☹
  • Investigations
    • Spirometry
    • Pre+post bronchodilator – to see if it resolves i.e. reversible (exclude asthma)
    • FBC (acute exacerbation of COPD = neutrophils)
    • Total lung capacity – body plethysmography
    • CXR = not very sensitive
      • Might show air-trapping
      • Might show mucopurelent changes
    • NB: Mucous sputum - check for current infection
    • NB: DLCO becomes bad if pulmonary fibrosis
  • He has had chronic CO2 retention and is no longer responsive to that. If we put him on 100% O2, he'll go into respiratory depression (his hypoxaemia is the only driver for his respiration)
  • Ventilation and (modest) diffusion defects
  • COPD = can slow the progression by stopping smoking, but they won't get better (they won't return FVC)
  • A lot of air trapping = emphysema; higher residual volume
  • COPD = chronic bronchitis + small airways disease + emphysema. Can have any or all of the components of this. If it's due to smoking, they usually have a few of each
    • Blue bloater = significant cyanosis (due to intrapulmonary shunting; resulting vasospasm to avoid the unventilated areas; results in pulmonary hypertension -->cor pulmonale & oedema therefore cyanosed and bloated) = Non-emphysema COPD.
    • Pink puffer = only pink in the sense that they're not blue (don't have intrapulmonary shunting), have predominantly emphysema, not as much shunting, not as much oedema. Hard to breathe out --> puffing to get out the last bit of air = Pure emphysema

A chest x-ray (linked from showed hyperinflated lung fields with diaphragmatic flattening. An emphysematous bulla (arrow) was evident in the left upper lobe. There were no mass lesions or areas of consolidation. Despite appropriate treatment, the man died six months later in respiratory failure, precipitated by an episode of infective bronchitis. Specimen 156.9 is representative of the appearances of his lungs at autopsy.

Task 7 Describe the macroscopic abnormalities in specimen 156.9. How would such changes lead to the clinical and investigative abnormalities in this case?

  • Emphysema bullae – periphery (don't know why)
  • Carbon deposits (fits with someone who is a smoker)
  • Lots of holes = spongey

Task 8 Outline the pathogenesis of this disease, emphasising the role of cigarette smoke in producing the structural abnormalities in the lung.

  • Smoking → increases proteases and decreases anti-proteases → disturbance of balance → inflammation → lose recoil of alveoli due to loss of elasticity (NB: can not make elastin again ☹)
  • NB: collagen remains along terminal bronchioles
  • NB: there is inflamattion at the beginning of emphysema + there is also some fibrosis
  • NB: bullae gets bigger → one-way air valve → air trapped → bullae gets bigger and lung keeps getting smaller
  • Microscopic changes (histopathology --> virtual slidebox --> additional other)
    • Lost lung tissue; no alveolar septa
    • Blunt-ended, broken alveolar septae (common in emphysema)
    • Patchy scarring in emphysema with lots of macrophages that have gobbled up carbon


Case History A 62 year-old former pipefitter presented to a respiratory physician due to progressive shortness of breath on exertion over the preceding six months. He had smoked 20 cigarettes per day for 40 years. A chest X-ray (linked from was reported to show calcified pleural plaques and interstitial fibrosis, consistent with asbestosis.

Task 9 How might this man’s occupation have led to inhalation of asbestos fibres? How could this have been prevented? How could the diagnosis of asbestosis have been confirmed?

  • Pipefitter
    • Asbestos will exist around the insulation of the pipes (Pipe Lagging → fibreglass strands)
    • Drilling and breaking = fibres become airborne
  • Preventative: full body suit + respirator
    • NB: VERY low level exposure can result in increased risk of mesothelioma etc. (there is NO safe level of exposure)
  • Confirming Diagnosis
    • CXR - linear streaking at lung bases, honeycomb changes
    • Biopsy
    • History
    • Sputum Smear → Check for asbestos bodies in sputum
      • Refer to last slide in associated lecture
        • NB: fibrosis with asbestosis is present
    • NB: IF hyaline mass present → consistent with bronchial carcinoma
  • Peak: workers in 60s and 70s where people were clueless or stupid with asbestos
    • Now: seeing renovation workers (e.g. pipefitters)
    • Spirometry
  • Asbestosis - asbestos-induced pulmonary fibrosis
  • CT scan: gold standard

Changes on CT/macro:

  • A) Fibrotic changes
    • Fibres carried into the pleura: pleural plaques
    • Parenchymal disease takes much higher level of exposure
  • B) Proliferative change
    • Thickened septal lines; huge nodule on pleura
    • Mesothelioma - any level of exposure
    • CT: wrap-around effect of the mesothelioma on the pleura. Mesothelioma = primary malignant tumour of pleura (also pericardium and peritoneum)
  • C) Cancer
    • Lung carcinoma (esp. with smoking)
    • Slide: pleural fibrosis, pulmonary fibrosis, mesothelioma, lung cancer and some infarcts

Task 10 Specimen 2048.8 shows one of the long-term complications of asbestos exposure. What abnormalities are present in the specimen? What other complications is this man at risk of developing?

  • Abnormalities
    • Nodular Tissue + Thickened Pleura
      • Thickened pleura wrapping around nodules → MESOTHELIOMA
      • Thick septa + huge shell of wrap-around
  • Complications
    • Mesothelioma
    • Bronchial carcinoma


  • Pulmonary function tests (especially spirometry; also diffusing capacity, lung volumes)
  • Full blood count
  • Imaging – mostly exclusion of other diagnoses
  • Arterial blood gases – in severe disease
  • Sputum culture – if persistent purulent sputum
  • Levels of alpha1-proteinase inhibitor – especially younger patients, non-smokers, family hx)