Flashcards in lecture 5 Deck (42):
What is the normal structure of the lung?
-- 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
What is the filtering capacity of different regions of the lung?
-- 5-10µ - nose/upper RT
-- 3-5µ - trachea & bronchi
-- <2µ - alveoli
Where do infections commonly occur in the lung? Where do dangerous infections tend to occur?
- 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
What features of the normal lung are important for gases to exchange efficiently?
- alveoli walls must be very thin (95% of alveolar surface area)
- massive surface area (about 35 times the surface area of the body)
What is the normal alveolar structure?
- 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
What happens when you have injury (infection) of the lung?
1. acute inflammatory response/s (rapid)
3b. chronic disease
Which areas of the lung are affected by pneumonia?
- pneumonias are respiratory disorders involving acute inflammation of the lung structures, such as the alveoli and bronchioles
How can we classify pneumonia?
According to causative agent:
- 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)
How does one get pneumonia?
- the development of pneumonia is facilitated by an exceedingly virulent organism, large inoculum, and impaired host defences
What are the normal host defences in the lung?
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
1. secreted IgA
2. IgM and IgG in alv fluid
- activate complement
3. accumulation of T cells - viral infections
How can lung defences be reduced?
- 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
How is pneumonia an opportunistic infection?
- usually occurs as a secondary infection in people who have other diseases/things that compromise their immune system e.g.
- transplant immunosuppression
- cystic fibrosis
- autoimmune disease
- old or young age
- chronic steroids
- 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)
What is the number one killer of children under 5 in the world?
What are some specific subtypes of pneumonia?
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
What are the differences between some of the pneumonia syndromes?
- 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
- Fungal species, e.g. candida, aspergillus
- chronic disease, immunosuppression, chemotherapy, irradiation
What organ is most affected by acute inflammation?
- the lungs - more than any other organ
What causes the largest amount of morbidity/work days lost?
What can pneumonia/acute inflammation produce?
- lobar pneumonia, bronchopneumonia, lung abscesses (& tuberculosis - chronic inflammation)
What determins the features of the acute inflammatory response in the respiratory tract?
The interaction between the organism and the host response
To what is the destructiveness of a lesion related?
- the organism invovled
- e.g. pneumococci vs. Klebsiella or staphylococci because of different host responses
What is acute inflammation?
- 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
What is chronic inflammation in contrast to acute?
- less uniform
- more complex and variable
- involves necrosis, inflammatory response and fibrosis
What are the components of acute inflammation?
- mast cell (not so much)
- polymorphonuclear leukocyte (neutrophils), appear rapidly
- complement components
What do chemokines released by macrophages do?
- attract other cells locally and maybe even via blood
- recruit other immune response cell types
- cascade/amplify inflammatory response, damage increases
What happens to blood vessels during acute inflammation?
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
How do we classify acute inflammation of the lung?
- suppurative (pus), fibrinous
- 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
What is the time course of acute inflammation?
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
Describe the histopathology of acute inflammation in the lung.
- 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
- the cellular component of the response is manifested by large numbers of leukocytes (neutrophils) in the alveoli
Describe the histopathology of stages of bacterial pneumonia
- 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
What are some complications that occur in pneumonia (especially lobar)?
- tissue destruction and necrosis
- spread of infection and inflammation to pleural cavity = Pleurisy
- bacteraemic dissemination
-- heart valves (endocarditis), pericardium (pericarditis), brain (meningitis), kidneys (nephritis)
What are symptoms of pleurisy?
- acute onset, malaise, fever, chills, productive cough
- chest pain secondary to pleurisy
- ARDS (Acute Respiratory Distress Syndrome)
How best to treat pleurisy?
- disease development dramatically changed by antibiotics
- ID of organism and antibiotic sensitivity are very important
What are the outcomes of acute inflammation?
1. Acute inflammation:
- vascular changes
- neutrophil recruitment
- limited tissue injury
- 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
- mononuclear cell infiltrate
- fribrosis (scar)
- progressive tissue injury
2d/3b/c. Healing --> fibrosis
- collagen deposition
- loss of function
- often in lung irreversible
What are the differences between acute and chronic inflammation in lung?
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
What is ARDS?
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
What causes ARDS?
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)
What is the big difference between ARDS and pneumonoa?
- always acute onset of respiratory failure
- almost always in ARDS bilateral infiltrate on CXR (some cases do present unilaterally or with pleural effusion
What are some differences in the immune response to ARDS?
- 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)
How does ARDS progress?
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
- 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
What are the possible outcomes of ARDS (where the patient lives)?
- 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)
What are mechanisms important in the resolution of ALI/ARDS?
- Na/K-ATPase = sodium pump
- ENaC - epithelial sodium channel
- aquaporins - water transport channels
- get rid of fluid build up and restore electrolyte balance