lecture 5

Question 1

What is the normal structure of the lung?

Answer 1

• airways:
• • mouth
• • nose
• • pharynx
• • larynx
• • trachea (anterior C-shaped plates of cartilage with posterior smooth muscle, mucous glands)
• • bronchi (discontinuous foci of cartilage with smooth muscle, mucous glands)
• • bronchioles (no cartilage or submucosal mucous glands, clara cells secreting proteinaceous fluid, ciliated epithelium)
• • alveolar duct (flat epithelium, no glands, no cilia)
• • alveoli (type I and II pneumocytes)
• branching of airways into alveoli is matched with a high level of capillaries and capillary networks that absorb oxygen from the alveolar cells
• you breath whatever is in the air
• each day constantly exposed to dust, chemicals, micro-organisms - breath 10,000 litres of air each day
• most individuals cope with this quite well as there are first line defences
• distal lung is normally quite sterile
• ciliated cells in bronchi and bronchioles help to eject a lot of the debris that we breathe in
• goblet cells that produce mucus: protective barrier against infection

Question 2

What is the filtering capacity of different regions of the lung?

Answer 2

• • 5-10µ - nose/upper RT
• • 3-5µ - trachea & bronchi
• • <2µ - alveoli

Question 3

Where do infections commonly occur in the lung? Where do dangerous infections tend to occur?

Answer 3

• most common infections seem to occur in bronchi/bronchioles (e.g. bronchitis)
• most dangerous infections seem to occur in alveoli - problems with transferring oxygen into blood

Question 4

What features of the normal lung are important for gases to exchange efficiently?

Answer 4

• alveoli walls must be very thin (95% of alveolar surface area)
• massive surface area (about 35 times the surface area of the body)

Question 5

What is the normal alveolar structure?

Answer 5

• critical anatomical area of the lung
• Type I pneumocytes cover 95% of the alveolar surface, very thin to allow for oxygen transfer
• Type II cells synthesise surfactant and are involved in the repair of alveolar epithelium through their ability to give rise to type I cells, surfactant gives the alveolar their structure, allows for transfer of oxygen and prevents them from collapsing
• resident macrophages - small numbers in homeostatic state
• capillaries (endothelial cells)
• rare monocytes/other WBCs

Question 6

What happens when you have injury (infection) of the lung?

Answer 6

1. acute inflammatory response/s (rapid)
2. pneumonia
   3a. recovery
   3b. chronic disease
   3c. death

Question 7

Which areas of the lung are affected by pneumonia?

Answer 7

• pneumonias are respiratory disorders involving acute inflammation of the lung structures, such as the alveoli and bronchioles

Question 8

How can we classify pneumonia?

Answer 8

According to causative agent:
Infectious:
- bacterial (the most common cause of pneumonia)
- viral pneumonia
- fungal pneumonia (rare)
Non-infectious (usually cause A.L.I)
- chemical pneumonia (ingestion or inhalation of irritating substance)
- inhalation pneumonia (aspiration pneumonia) (breathing in high acid gastric contents)

Question 9

How does one get pneumonia?

Answer 9

• the development of pneumonia is facilitated by an exceedingly virulent organism, large inoculum, and impaired host defences

Question 10

What are the normal host defences in the lung?

Answer 10

Innate:

1. mucus blanket - mucu-ciliary escalator + cough reflex
2. phagocytosis - alveolar macrophages
3. phagocytosis - recruited neutrophils
4. complement - C3b - MAC
5. draining lymph nodes - initiation of immune response

Acquired:

1. secreted IgA
2. IgM and IgG in alv fluid
   - activate complement
   - opsonise
3. accumulation of T cells - viral infections

Question 11

How can lung defences be reduced?

Answer 11

• pneumonia occurs when these defences are impaired &/or host resistance decreased
• e.g. smoking, chronic alcohol, viral infection, chronic disease, treatment with immunosuppressive agents, diabetes, malnutrition, wasting diseases, interferences with phagocytic ability of alveolar macrophages (genetic/acquired) etc
• one type of RT infection pre-disposes to another
• many with terminal disease –> fatal pneumonia
• antibiotic resistant bacteria and invasive procedures –> spread
• loss/suppression of cough reflex via - coma, anaesthesia, neuromuscular disorders, drugs, chest pain - can lead to aspiration of gastric contents
• injury to muco-ciliary apparatus
  via - T-smoke, viral infection, inhalation of hot/corrosive gases, genetic abnormalities (e.g. immotile cilia syndrome)
• interference with phagocytic/anti-bacterial action of alveolar macrophages
  via - alcohol, T smoke, anoxia, or O2 intoxication, genetic abnormality
• accumultion of secretions - e.g. cystic fibrosis, bronchial obstruction (e.g. tumour), stroke
• pulmonary congestion or oedema: due to chronic heart disease

Question 12

How is pneumonia an opportunistic infection?

Answer 12

• usually occurs as a secondary infection in people who have other diseases/things that compromise their immune system e.g.
• AIDS
• alcoholics
• transplant immunosuppression
• pregnancy
• alcoholism
• cystic fibrosis
• autoimmune disease
• burns
• cancer
• chemotherapy
• old or young age
• chronic steroids
• diabetes
• some bacteria seem to cause widespread damage to the lungs (e.g. cytomegalovirus) while others seem to cause focal infection (e.g. gram-negative rods)

Question 13

What is the number one killer of children under 5 in the world?

Answer 13

Pneumonia

Question 14

What are some specific subtypes of pneumonia?

Answer 14

Community-acquired acute pneumonia

• e.g. Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila
• large volume of inflammatory exudate in alveoli and airways

Community-acquired atypical pneumonia

e. g. Mycoplasma, Chlamydia, viruses (influenza A & B)
- smaller amounts of exudate - patchy - in alveolar interstitium

Nosocomical Pneumonia (hospital acquired)

• e.g. Enterovactiaceae: Klebsiella pneumoniae, E. coli, Pseudomonas pneumoniae, Staphlococcus aureus (penicillin-resistant)
• due to chronic disease &/or immunosuppression, invasive procedures, resistant organisms

Question 15

What are the differences between some of the pneumonia syndromes?

Answer 15

Chronic pneumonia

• fungal species e.g. Nocardia
• Intracellular bacteria e.g. Mycobacterium tuberculosis
• often granulomatous inflammatory response

Aspiration pneumonia (necrotising)

• most often in debilitated patients
• those who aspirate gastric contents
• chemical and bacterial

Pneumonia in immunocompromised host

• Cytomegalovirus
• Pneumocystis
• Fungal species, e.g. candida, aspergillus
• chronic disease, immunosuppression, chemotherapy, irradiation

Question 16

What organ is most affected by acute inflammation?

Answer 16

• the lungs - more than any other organ

Question 17

What causes the largest amount of morbidity/work days lost?

Answer 17

• Pneumonia

Question 18

What can pneumonia/acute inflammation produce?

Answer 18

• lobar pneumonia, bronchopneumonia, lung abscesses (& tuberculosis - chronic inflammation)

Question 19

What determins the features of the acute inflammatory response in the respiratory tract?

Answer 19

The interaction between the organism and the host response

Question 20

To what is the destructiveness of a lesion related?

Answer 20

• the organism invovled

- e.g. pneumococci vs. Klebsiella or staphylococci because of different host responses

Question 21

What is acute inflammation?

Answer 21

• inflammation is a series of changes in response to injury in vascularised living tissue
• acute: short-lived (hours, days), stereo-typed
• causes: anything that causes injury
• variations: severity, site of injury, host response
  purposes: to dilute and destroy agent/s of injury, to initiate repair

Question 22

What is chronic inflammation in contrast to acute?

Answer 22

• less uniform
• more complex and variable
• involves necrosis, inflammatory response and fibrosis

Question 23

What are the components of acute inflammation?

Answer 23

• mast cell (not so much)
• macrophage
• polymorphonuclear leukocyte (neutrophils), appear rapidly
• monocyte
• complement components

Question 24

What do chemokines released by macrophages do?

Answer 24

• attract other cells locally and maybe even via blood
• recruit other immune response cell types
• cascade/amplify inflammatory response, damage increases

Question 25

What happens to blood vessels during acute inflammation?

Answer 25

1. vascular dilation and increased blood flow (causing erythema and warmth) 2. extravasation and extravascular deposition of plasma fluid and proteins (edema) - tight junctions replaced by gaps 3. leukocyte migration and accumulation at the site of injury

Question 26

How do we classify acute inflammation of the lung?

Answer 26

Agent: - pneumococcal - staphylococcal Host response: - suppurative (pus), fibrinous Anatomical distribution - lobar (whole lobe) or broncho (focal inflammatory response throughout the lung but in small patches) - clearly seen in x-ray - lobar rarely occurs in both lungs

Question 27

What is the time course of acute inflammation?

Answer 27

1-2 days: lung heavy, full of blood - oedema 2-4 days: lung red, heavy, full of liquid and some fibrin – stasis and congestion = red hepatisation 4-8 days: lung solid, heavy, grey-white = grey hepatisation, alveoli full of fibrin and neutrophils, red cells disintegrate > 8 days: Resolution - exudate breaks down and is removed

Question 28

Describe the histopathology of acute inflammation in the lung.

Answer 28

Normal: - thin (virtually invisible) blood vessels in the alveolar walls and no cells in the alveoli Vascular congestion and stasis: - the vascular component of acute inflammation is manifested by congested blood vessels (packed with erythrocytes) resulting from stasis Leukocyte infiltrate: - the cellular component of the response is manifested by large numbers of leukocytes (neutrophils) in the alveoli

Question 29

Describe the histopathology of stages of bacterial pneumonia

Answer 29

- the congested septal capillaries and extensive neutrophil exudation into alveoli corresponds to early red hepatisation. Fibrin nets have not yet formed - early organisation of intra-alveolar exudate, seen in areas to be streaming through the pores of Kohn (openings that connect alveoli together) - advanced organising pneumonia featuring transformation of exudates to fibrous masses richly infiltrated by macrophages and fibroblasts

Question 30

What are some complications that occur in pneumonia (especially lobar)?

Answer 30

- tissue destruction and necrosis - spread of infection and inflammation to pleural cavity = Pleurisy - bacteraemic dissemination - - heart valves (endocarditis), pericardium (pericarditis), brain (meningitis), kidneys (nephritis)

Question 31

What are symptoms of pleurisy?

Answer 31

- acute onset, malaise, fever, chills, productive cough - chest pain secondary to pleurisy - ARDS (Acute Respiratory Distress Syndrome)

Question 32

How best to treat pleurisy?

Answer 32

- disease development dramatically changed by antibiotics | - ID of organism and antibiotic sensitivity are very important

Question 33

What are the outcomes of acute inflammation?

Answer 33

1. Acute inflammation: - vascular changes - neutrophil recruitment - limited tissue injury 2a. Resolution - Clearance of injurious stimuli - clearance of mediators and acute inflammatory cells - replacement of injury cells - normal function 2b. Pus formation (abscess) 1/2c. Chronic inflammation - angiogenesis - mononuclear cell infiltrate - fribrosis (scar) - progressive tissue injury 2d/3b/c. Healing --> fibrosis - collagen deposition - loss of function - often in lung irreversible

Question 34

What are the differences between acute and chronic inflammation in lung?

Answer 34

Chronic 1. collection of chronic inflammatory cells 2. destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium: limited capacity to transfer oxygen) 3. replacement of connective tissue (fibrosis) - by contrast, in acute inflammation of the lung neutrophils fill the alveolar spaces and blood vessels are congested - rapidly reversible

Question 35

What is ARDS?

Answer 35

Acute Respiratory Distress Syndrome aka: shock lung, traumatic wet lungs, diffuse alveolar damage - separate to pneumonia - high mortality: 40% - 60% - ARDS = the end result - it is the effect of wide-spread, diffuse damage to alveolar capillaries, epithelium, and surfactant layer - can arise as a complications of diverse situations either direct injury to the lung or systemic disorders

Question 36

What causes ARDS?

Answer 36

Direct Lung Injury: - gastric aspiration - pulmonary contusion, penetrating lung injury - ionising radiation - near drowning - inhalation injury e.g. NO2, SO2, Cl2, smoke - reperfusion pulmonary edema after lung transplant - oxygen toxicity (SCUBA divers)

Question 37

What is the big difference between ARDS and pneumonoa?

Answer 37

- always acute onset of respiratory failure | - almost always in ARDS bilateral infiltrate on CXR (some cases do present unilaterally or with pleural effusion

Question 38

What are some differences in the immune response to ARDS?

Answer 38

- lots of cellular debris: rapid necrosis occurring in Type I alveolar cells - denudation of epithelial cells further up - sack like structure with almost no living cells - loss of surfactant proteins - infiltration of immune cells similar to pneumonia - massive amount of apoptosis in Type I cells - almost complete suppression of Bcl2, increases in Bax, Caspase-3, TUNEL (last three pro-apoptotic)

Question 39

How does ARDS progress?

Answer 39

2 phases: exudative and organising 1. exudative (acute) day 1: interstitial/alveolar oedema, degenerative changes in type 1 alveolar epithelium, start of interstitial infiltrate - lymphocytes, plasma cells, macrophages day 2: sloughing type 1 cells: bare basement membrane, hyaline membranes begin day 4-5: peak of hyaline membrane formation day 7: - peak of interstitial inflammatory infiltrate - type 2 alveolar epithelial cells proliferate and spread along basement membrane - thrombi in alveolar capillaries and pulmonary arterioles 2. organising phase (slower) (if patient is alive) - interstitial inflammation and type II hyperplasia persist - macrophages breakdown hyaline membrane and debris day 10: interstitial fibroblasts proliferate, produce collagen - you see granulation tissue in alveolar spaces and chronic inflammatory infiltrate , lots of collagen in the ECM

Question 40

What are the possible outcomes of ARDS (where the patient lives)?

Answer 40

1. Resolution - complete recovery and restoration of normal lung function - alveolar exudate and hyaline membrane resorbed - normal alveolar epithelium restored - fibroblast proliferation ceases - extra collagen metabolised - broken up and destroyed 2. End-stage fibrosis - exudate associated with tissue destruction (i.e. the hyaline membranes – large amount of scar tissue produced, lung architecture remodelled) - multiple cyst-like spaces = 'honeycomb lung' (spaces separated from each other by fibrous tissue, lined with type II epithelium, bronchiolar epithelium or squamous cells)

Question 41

What are mechanisms important in the resolution of ALI/ARDS?

Answer 41

- Na/K-ATPase = sodium pump - ENaC - epithelial sodium channel - aquaporins - water transport channels - get rid of fluid build up and restore electrolyte balance

Question 42

How do we treat ARDS?

Answer 42

- mechanical ventilation - inhalation of NO - causes bronchodilation - high O2 concentrations - toxic - surfactant therapy - anti-inflammatory drugs - glucocorticoids - treatment very difficult - mortality in 40 - 60% of patients - stem cell treatment prospects: have shown that mesenchymal stem cell conditioned medium (ie the liquid the stem cells were grown in) is very effective in restoring the lung, therefore it is something the stem cells are making