Respiratory

Lung cancer:

Epidemiology-

Third most common cause of death in the uk

Quarter of all cancer deaths

Mutational Compensation :

Our cells want to become immortal but there are certain house-keeping genes which induce

so that the cell don't go out of control Viral oncogenes in combination with smoking make these cells become more proliferative

Trends in Smoking Prevalence and Mortality:

There has been a steady decline in smoking prevalence among men over the years The peak prevalence for women was about 15 years later

This is translated to the mortality we see with lung cancer Mortality in men is declining over time Mortality in women continued to peak and then started declining now

Clinical Features of Lung Cancer:

-coughing up blood

Unexplained or persistent (more than 3 weeks): Cough Chest/Shoulder pain Chest signs Dyspnoea Hoarseness Finger clubbing

Nail bed should be less than 180 degrees If it is greater than 180 degrees then that could be a sign of lung cancer

Staging - TNM Classification :

Tumour, Nodes, Metastases

The location of the tumour is also indicated in T staging

If the tumour is closer to the mediastinum or the chest wall then it has a

T staging

So you T staging is based on location, size and proximity to other organs

If the tumour spreads to the lymph nodes in the neck then there is higher staging Surgery is not practical if the cancer has spread to the lymph nodes

PET Scans:

Patients fast for 4 hours and are then given radiolabelled

The lung as a whole is not very active but the tumour is very metabolically active and hence show up very clearly The kidneys are naturally very metabolically active

Metastasis:

Much of the M staging will be evident from looking at scans

There could be a lot of tumour in the lymph nodes near the

which could lead to the patients getting a throbbing head and a build up of pressure in the superior venous system

Algorithm for Small Cell Lung Cancer:

Diagnose ---> Stage ---> Treat

Treatment is based on the cell type of the tumour, the extent of the tumour (TNM), how fit the patient is (are there co-morbidities, are they fit for surgery)

Small Cell Lung cancer usually grows

and metastasise early - treatment involves chemotherapy and radiotherapy

If they are very debilitated, they might be given palliative radiotherapy If the tumour disappears, you give prophylactic brain radiotherapy

Algorithm for Local Non-Small Cell Lung Cancer

If it is localised, then the best treatment is

Algorithm for Advanced Non-Small Cell Lung Cancer

If there is advanced disease with lymph node involvement you'd give chemotherapy to begin with to try and reduce the extent of the spread

Natural History of Lung Cancer:

Prognosis depends on the cell type and the extent of the spread Earliest time point when we can make a diagnosis is when the tumour is around

Most patients present when the tumour is around 30 mm Some tumours grow very slowly - adenocarcinomas grow extremely slowly

Clinical Presentation:

Most patients will be

There may be incidental findings of a mass on the chest X ray

Symptomatic: Cough Haemoptysis Recurrent infections Chest wall pain

Making the Diagnosis

Pathologists can look at individual cells which is known as

or look at tissues- histology

Cytology: Sputum Bronchial washings and brushings Pleural fluid (if the tumour is peripheral it can irritate the pleura and make it produce fluid) Endoscopic fine needle aspiration of tumour/enlarged lymph nodes

Histology: Biopsy at bronchoscopy - central tumours Percutaneous CT guided biopsy - peripheral tumours Mediastinoscopy and lymph node biopsy - for staging Open biopsy at time of surgery if lesion is not accessible otherwise - frozen section Resection specimen - confirm excision and staging

Lung Tumour Types

Tumours arise from a variety of cell types: epithelial, mesenchymal (soft tissue), lymphoid

lung tumours- Don't metastasise, Can cause local complications e.g. obstruction of the airways EXAMPLE: chondroma

Malignant Lung Tumours Have potential to metastasise Invade adjacent tissues MOST COMMON: Epithelial Tumours

Common Malignant Epithelial Tumours of the Lung

Non-small cell carcinoma has

types: Squamous Cell Carcinoma (20-40%) Adenocarcinoma (20-40%) Large Cell Carcinoma (uncommon)

Small Cell Carcinoma (20%) Much worse prognosis than non-small cell It is unusual to find an early stage small cell carcinoma because they grow rapidly and metastasise early

Incidence of Non-Small Cell Carcinoma:

Incidence of squamous cell carcinoma is

Incidence of adenocarcinoma is

Adenocarcinoma is the most common form of lung cancer among

So as incidence of smoking decreases, the proportion of lung cancer that is attributed to adenocarcinoma increases This could also be due to a change in the type of cigarettes smoked - years ago, the cigarettes had a large amount of tar so people couldn't breathe it in as deeply

Squamous cell carcinomas tend to arise near the mediastinum

Adenocarcinoma tends to arise in the

Aetiology of Lung Cancer:

Smoking (at least 75% attributable - 25% of non-smokers attributed to passive smoking) Tumour initiators Polycyclic aromatic hydrocarbons Tumour promoters N Nitrosamines Nicotine Phenols Complete carcinogens Nickel, Arsenic

Asbestos Exposure (asbestos + smoking = 50 fold increased risk) Radiation (radon exposure, therapeutic radiation) Rare metals (chromates, arsenic, nickel, mustard gas)

Genetic Predisposition:

Familial lung cancers are very

However, there are susceptibility genes: Nicotine addiction Chemical modification of carcinogens Polymorphisms in cytochrome p450 enzymes and glutathione S transferases which play a role in eliminating carcinogens Susceptibility to chromosome breaks and DNA damage

Development of Carcinoma

Multistep pathway changes from: Metaplasia Dysplasia Carcinoma in situ Invasive carcinoma

Associated with the accumulation of mutations There are different pathways for different types of tumours Some of the early stages are reversible e.g. if you have early stage dysplasia

Squamous Cell Carcinoma: Pathway of Development

Squamous cell carcinoma tends to arise in the

The airway epithelium reacts to the chronic irritation of cigarette smoke - the epithelium changes and becomes

The ciliated epithelium is quite delicate so if it is repeatedly exposed to smoke it will change to

epithelium

As there is no cilia on the epithelium any more, the mucus will stay in your lungs so you get smoker's cough

The squamous cells begin to acquire mutations which means that its normal pattern of growth is disrupted

The dysplasia becomes more and more disordered so it becomes carcinoma

A further mutation will make it invasive

General Notes on Squamous Cell Carcinoma:

Accounts for 25-40% of lung cancer Closely associated with

Traditionally central arising - from bronchial epithelium but recently there has been an

in peripheral squamous cell carcinoma

They tend to spread distally in the lungs before spreading to the lymph nodes

Cytology of Squamous Cell Carcinoma:

The irregular cells have large

and there is

in the cytoplasm

Shows evidence of squamous differentiation: Keratinisation and intracellular prickles represent desmosomes

Adenocarcinoma development:

Forms from

epithelium, tends to develop in the

and are increasing in incidence because of deeper inhalation of cigarette smoke and because it is more common in non-smokers

The precursor lesion is atypical adenomatous hyperplasia

Atypical Adenomatous Hyperplasia = proliferation of atypical cells lining the

increases in size and eventually can become invasive

Progression of Atypical Adenomatous Hyperplasia:

Over time some of the atypical cells lining the alveolar walls grow larger and they

invasive

At some point, the cells will mutate and be able to form enzymes that break down the

Breaking down the stroma forms fibrous scars and is accompanied by

Once the adenocarcinoma has become invasive, it has potential to spread around the body

The invasive tumour can break down the elastin in the basement membrane and form the pink fibrous stroma

Cytology of Adenocarcinoma:

It's an adenocarcinoma so it has to show some evidence of glandular differentiation. Glandular epithelium often produces

Histology of Adenocarcinoma

Increasing incidence, 25-40% of pulmonary carcinomas

Commoner in far east, females and non-smokers. Peripheral and more often metacentric

It is often multi-focal in the lungs They tend to spread early

Molecular pathways in adenocarcinoma:

There are two pathways, one is associated with smoking and the other with non-smoking: Smoker =

mutation (DNA methylation)

Non-Smoker = EGFR mutation/amplification (Epidermal Growth Factor Receptor)

If the patient has a K ras mutation then they

going to respond to targeted therapy (like Tarceva)

If it is an EGFR mutation, you need to see whether it is a responder mutation or a resistance mutation

Some patients with responder mutation with quite advanced disease (metastasis and large tumour) can show almost complete regression with these targeted therapies

Large cell carcinomas:

Poorly differentiated tumours composed of

cells, no histological evidence of glandular or squamous differentiation

But on electron microscopy, many show evidence of glandular, squamous or neuroendocrine differentiation

Small cell carcinoma:

Cytology- This is the worst form of lung cancer

Small cell lung cancer consists of, as the name suggests, small cells. They are basically just nuclei with a small amount of cytoplasm

Histology of small cell carcinoma

20-25% of all lung cancer, often near the

Very close association with

80% of cases present with advanced disease Although very chemosensitive - there is an awful prognosis

Because they divide so fast, the tumour often outgrows its blood supply and becomes

Importance of Histological Tumour Type:

Small Cell Lung Carcinoma : Survival 2-4 months untreated Survival 10-20 months with current treatment. Treated with

Non-Small Cell Lung Carcinoma: Early Stage 1: 60% 5 year survival Late Stage 4: 5% 5 year survival 20-30% have early stage tumours suitable for surgical resection Less chemosensitive

New data suggests that it is becoming increasingly important to SUB-TYPE non-small cell carcinoma for treatment

Some adenocarcinomas respond well to anti-

drugs (e.g. Tarceva) In contrast, some patients with squamous cell carcinoma develop fatal haemorrhage with Bevacizumab

TNM staging system:

T is for

Size, invasion, pleura, invasion of other structures

N is for

N0 - lymph node not involved by tumour N1 or N2 or N3- lymph nodes involved by tumour

M is for

This is a measure of how advanced the tumour is The TNM staging is used to determine prognosis and operability

Tumour staging can be clinical, radiological or

Molecular therapeutics:

Molecular changes in lung cancer provide: Prognostic data Therapeutic data Predict response to conventional chemotherapy Find targets for novel drugs

Single genes vs gene microarrays

Predictors of Response to Conventional Chemotherapy :

E.g. Excision Repair Cross-Complimentation Group 1 Protein (ERCC1)

This marker determines response to

In advanced stage non-small cell lung cancer, ERCC1 positive tumour have

response to cisplatin based chemotherapy

ERCC1 protein removes drug-DNA adducts (covalent links between drug and DNA)

Targets of Treatment - EGFR (Epidermal Growth Factor Receptor):

EGFR sits on the surface of cells and signals a variety of downstream pathways that make the cell divide

You can get mutation or amplification of EGFR, mainly in adenocarcinoma

EGFR is a type of membrane receptor

It regulates angiogenesis, proliferation, apoptosis and migration EGFR is the target of a tyrosine kinase inhibitor

Symptoms, signs and complications of Lung Cancer:

Local Effects of Bronchogenic Carcinoma-

If you have a proximal tumour then it is likely to be squamous cell carcinoma or small cell carcinoma

A proximal tumour could cause

obstruction which could lead to:

Collapse of the distal lung Leads to shortness of breath

Impaired drainage of the bronchus Chest infection - pneumonia, abscess

Invasion of local structures

Extension through pleura or pericardium and diffuse lymphatic spread within lung

An exaggerated response that may be immunological or non-immunological-

Immunological – i.e. allergy; may be IgE-mediated (e.g. atopic diseases including hayfever, eczema, asthma) or non—IgE-mediated (e.g. farmers lung)

Non immunological – intolerance (e.g. food), enzyme deficiency (e.g. lactase DH), pharmacological (e.g. aspirin hypersensitivity)

an exaggerated immunological response to a foreign substance (allergen) which is either inhaled, swallowed, injected, or comes in contact with the skin or eye-

An allergy is a mechanism, not a disease, but the mechanisms often play a temporary or permanent role in disease

Can be subdivided into different categories: o Asthma o Drug reactions o Food reactions o Rhinitis o Eczema, urticaria (hives), angioedema (swelling similar to hives, but not on surface of skin)

“out of place”; the hereditary predisposition to produce IgE antibodies against common environmental allergens-

The atopic diseases are allergic rhinitis, asthma + atopic eczema • Allergic tissue reactions in atopic subjects are characterised by infiltration of Th2 cells and eosinophils • The term “allergic match” is used to describe the common progression from atopic dermatitis to allergic asthma

IgE-mediated allergic reactions in the upper and lower airways:

May present with either acute or chronice symptoms of allergy

Acute symptoms result from the binding of allergen to

-coated mast cell, which causes mast cell degranulation and release of

Chronic symptoms present from the interaction of the allergen with antigen-presenting-cells – involving the release of Th2 cytokines and chemokines

Th2 responses:

Involves the collaboration between innate and adaptive immune responses

PAMPs present on allergen interact with barrier cells e.g. epithelial cells lining airway - stimulates secretion of IL-33 and IL-25

Interleukins attract natural helper cells, nuocytes and MPPtype2 cells

These cells then secrete IL-4, IL-5 + IL-13, which induces

cell differentiation,

cell proliferation and anti-allergen effector functions – this is where the adaptive immune response is involved

Th2 cell is CD4+, therefore releases: o IL-4 leads to synthesis of

o IL-5 leads to development of

IL-9 leads to development of

IL-13 leads to IgE synthesis + airway hyperresponsiveness

Allergic diseases:

Allergic diseases include: Atopic allergy (IgE mediated) • Allergic asthma – including occupational • Allergic rhinitis – including hay fever • Anaphylaxis - e.g. food, insect stings, drugs, latex • Skin allergies – e.g. urticaria, angioedema, atopic eczema

Non-atopic allergy (IgG mediated/T-cell mediated) • Contact dermatitis • Extrinsic allergic alveolitis • Coeliac disease

Non-allergic hypersensitivity/intolerance responses:

Usually apply to intolerance to

Non-immunological mechanisms

E.g. include enzyme deficiency (Lactase DH), migraine (triggered by coffee, wine), IBS (exacerbated by various foods), bloating due to wheat intolerance

Allergic rhinitis:

can be either seasonal or perennial -triggered

characterised by a blocked or runny nose, sneezing, itching and streaming eyes

Seasonal allergic rhinoconjunctivitis (more commonly referred to as hayfever), is caused by allergenic substances contained within

Worst symptoms usually at the height of summer when vast clouds of grass pollens become airborne. Due to mild winters and warmer springs, pollination of grasses in the United Kingdom is now starting earlier therefore the worst symptoms can be well established by the first week in June and tend to peak around mid-June to early July.

When the pollen counts are very high, some wheeziness can also co-exist with rhinitis, in a condition known as seasonal allergic asthma.

Perennial allergic rhinitis involves troublesome chronic symptoms such as a blocked, runny nose and sneezing.

Can have non-allergic causes of perennial rhinitis such as

and structural abnormalities, and a small minority of patients have underlying immunodeficiency problems too.

allergy to the house dust mite (Dermatophagoides species) and allergens derived from animals such as cats, dogs, horses and pet rodents are the most important causes

Asthma:

Definition: chronic disorder characterized by episodes of

breathlessness but which may also present as an isolated cough

Aetiology - still uncertain, but the pathology involves

of the large and small airways (bronchi and bronchioles).

Clinical presentation: A wide clinical spectrum of asthma symptoms result, ranging from mild occasional wheezing, which is usually controlled by the occasional use of inhaled bronchiodilators, through to severe intractable disease which requires treatment using systemic

General anaphylaxis:

Symptoms: • Dizziness, seizures, loss of consciousness • Anxiety, sense of gloom • Arrhythmia • Vomiting, diarrhoea, pain • Urticaria/hives • Tingling in hands and feet • Bronchoconstriction • Laryngeal oedema • Lip, tongue swelling

Causes: • Drugs, e.g. pencillin • Foods, e.g. peanuts, tree nuts, milk, eggs, fish, shellfish, sesame seeds, soybeans, celery, celeriac • Insect stings e.g. bees, wasps, hornets • Latex

Treatment: use of an

Extrinsic allergic alveolitis (EAA):

Definition: Extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis (HP) is a non-IgE T cell mediated inflammatory disease effecting the alveoli and interstitiuM – Affects 0.1% population

Cause: It occurs in susceptible people following the repeated inhalation of certain antigens. These antigens typically include bacterial or fungal microorganisms in the workplace or bird antigens. Some antigens that cause asthma such as the mold, alternaria, can also induce EAA.

The prevalence of EAA varies and is related to the particular

and the host immune response

Studies have shown that, a minority of individuals exposed develop disease. Cytokine gene polymorphisms in the TNF-alpha promoter region appear to be a host susceptibility factor.

Establishing the diagnosis of EAA is challenging requiring a high index of suspicion, a thorough history, careful examination, complete pulmonary function tests and radiographic studies.

The histology reveals a lymphocytic infiltrate with a predominance of CD8+ lymphocytes, “foamy” alveolar macrophages, and granulomas consistent with nonspecific interstitial pneumonia.

Early identification of patients with EAA with subsequent avoidance of the causative antigen is the key to a successful outcome.

Pharmacologic treatment for acute EAA is limited to

and oral corticosteroids

Oral steroids may not affect the long-term outcome. The prognosis is generally favorable if intervention takes place before pulmonary

occurs

Overlap of atopic disease

Prevalence:

• 5.7 mil diagnosed with asthma at some point • 1/15 people recorded diagnosis of allergic

117% increase in no suffering from peanut allergy from 2001-2005

No of hospital admissions due to anaphylactic shock increased 7x from 1990-2000

Trends:

in infectious diseases mirrors an increase in allergy and autoimmune disease

Burden:

allergic disorders can make social interactions difficult as even simple everyday activities can pose a major health risk

Allergies affect all aspects of a patient’s life. Hayfever symptoms disrupt children’s

and often impair their performance at school and asthma has been associated with school absenteeism.

Allergy patients often find it difficult to live a normal life. This is especially apparent in children, where special care has to be taken whilst engaging in everyday activities which in turn induces anxiety and impairs the quality of life.

The prevalence of allergic disease has markedly increased over recent years. In the UK, by 2004, the scale of the “allergy epidemic” was such that 39 per cent of children and 30 per cent of adults had been diagnosed with one or more of asthma, eczema and hayfever, and 38 per cent of children and 45 per cent of adults had experienced symptoms of these disorders in the preceding 12 months.

Marked increase in prevalence indicates importance of

influences in addition to genes

Hygiene hypothesis: developing immune system is deprived of the microbial antigens that stimulate Th2 cells, because the environment is relatively clean and because of childhood vaccinations and the widespread use of antibiotics for minor illnesses in early life. This is in addition to a genetic predisposition to asthma involving chromosome 5,6,11,12 + 14

Atopy and allergic asthma were

frequent in people exposed to agents in soil, air and water such as H. pylori, T. gondii, hepatitis A virus.

Also a traditional lifestyle with a high gut bacterial turnover rate and intestinal colonisation with lactobacilli and bifidobacteria protect against allergy. Such a lifestyle is usually associated with "organic" food including spontaneously fermented vegetables.

Other related factors which may encourage the Th2 phenotype include a date of birth around the pollen season, and alterations in infant diet.

Furthermore, atopic allergic diseases are

common in younger siblings and larger sibships and in those who have had measles and hepatitis A indicating that repeated “immune stimulation” (e.g. by viruses) may be protective.

The development of specific allergic diseases may be related to alterations in the target organ

Principles of treatment of allergic airway diseases, including allergen specific immunotherapy:

Consists of: allergen avoidance, anti-allergic medication + immunotherapy

Anti-allergic medication:

used to relief rhinitis symptoms, and topical corticosteroids (anti- inflammatory). o Histamine1-receptor antagonists less sedative + more selective than old antihistamins

Administering increasing concentrations of allergenic extracts over long periods of time.-

• Advantages – effective and produces long lasting immunity • Disadvantages – risk of developing anaphylaxis (particularly during induction), time consuming, standardisation problems

Attempts to minimize systemic reactions include pre-treatment of allergen extracts with agents like formaldehyde (allergoids). However this results in reduced immunogenicity as well as a decrease in

binding

Indications for use: gass/tree pollen allergic rhino-conjuctivitis uncontrolled by medication, bee/wasp sting anaphylaxis at risk for repeats • Mode of action is complex, but central to its principle is down-regulation and up-regulation:

What is the difference between Hypoxia and Hypoxaemia?

These terms can sometimes be used interchangeably but on some occasions they have very different meanings

describes the blood environment

Anything below

kPa can be considered to be hypoxaemia

What factors can put your body under hypoxic stress? Disease - if you impede the ability of outside air to get to the cells Altitude - if the air you're breathing in has a low oxygen content, then that reduces the starting point of the oxygen cascade

Review of oxygen transport:

You begin with ambient air with a partial pressure of 21.3 kPa (this is 20.9% of total atmospheric pressure)

As altitude increases - barometric pressure

and this partial pressure decreases due to

law (partial pressure of the environment is the sum of the partial pressures of the gases involved)

As the air moves into to the airway, it becomes

As it goes down the different generations of airways - from conducting to respiratory airways - it mixes with the gases that are already in there (remember there is a bit of air that always remains in the lungs - this is why we can hold our breath)

If we take a deep breath in and hold it - the oxygen will keep moving into the blood until the gradient is lost

IMPORTANT POINT: blood arrives at the gas exchange surface

saturated with a partial pressure of 5.3kPa

It is then fully oxygenated to

kPa

The lungs have their own blood supply to keep them alive - they don’t get this via the pulmonary circulation, this is a separate thing

This bronchial drainage returns to the pulmonary veins and dilutes the blood so the saturation decreases slightly to

%

As the blood circulates through the lungs, it is going to become equilibriated to match the tissues (wherever there's a gradient) - oxygen will move in and carbon dioxide will move out

Mean PO2 in the alveolar space and in the arterial blood

with age

Oxygen dissociation curve:

There is a range of partial pressures in the lungs but the shape of the ODC is such that we can fully oxygenate the blood even if the partial pressure in the lungs is lower when you're older

P50 - gives the overall impression of the position of the curve at any point - this can be used to determine whether it is a loading or an unloading environment

Essentially, the position of the ODC varies depending on how much

is happening

The curve can also move up and down in which case the P50

change

Polycythaemia = an abnormally increased concentration of

in the blood

Polycythaemia could be due to reduction of plasma volume or an increase in red cell numbers (it causes an increased haematocrit)

If you have more haemoglobin then your ODC will go

Anaemia will cause the ODC to move down

the haemoglobin is still 100% saturated but the total O2 in the blood changes

The oxygen cascade:

The Oxygen Cascade describes the decreasing oxygen tension from inspired air to respiring cells

The amount of gas that'll diffuse across a membrane is proportional to: Surface area for gas exchange Diffusion constant (CO2 diffuses faster than O2) Diffusion gradient

You start with

kPa of oxygen at atmospheric pressure

Humidification - we lose a little bit of oxygen when we humidify the air in our airways

As you go further down the airways you mix with the air that is already in the airways This bar can be moved UP (hyperventilation) or DOWN (hypoventilation)

There should be

change between the alveolar air and the post-alveolar capillaries (provided you can get the air to your alveoli you should be able to get it to your arteries)

There is a slight decrease between post-alveolar capillaries and arteries because of the bronchial

About 1% of the cardiac output on your arterial side ends up perfusing the bronchial tree and this 1% gets dumped back into the circulation and causes a slight decrease in saturation The difference between arteries, veins and tissues depends on the demand at the time

In tissues, the PO2

with increased exercise

ARTERY PO2 = 13.3 kPa VEIN PO2 = 5.3 kPa

25% of the haemoglobin desaturates when going from the arteries to the veins

% of oxygen is transported in the blood bound to haemoglobin, the rest is dissolved

The dissolved oxygen doesn't really contribute to the oxygen delivery itself but it acts like the 'conductor of an orchestra' - it controls everything else

The big drop in partial pressure of oxygen from the arteries to the tissues isn't keeping you alive directly, but this drop in partial pressure is associated with a big unloading of haemoglobin which is associated with a whole load of oxygen

Factors affecting the oxygen cascade:

Alveolar Ventilation Ventilation/Perfusion Matching - if you are ventilating airways that are not perfused or hyper-perfused, you wont achieve efficient gas exchange. If you perfuse unventilated alveoli then you're going to leave with the same saturation that you came with Diffusion Capacity - some disease can affect the

(the functional subunits - the alveolar capillary membranes)

Cardiac Output - if you increase cardiac output then you increase the amount of blood flowing through and getting the opportunity to oxygenate hence increasing oxygen delivery

If you're breathing hypoxic air, your exercise capacity

Exercise:

10 seconds uses ATP and ATP-Phosphocreatine system - you don't really need to breathe 400 m = Lactic Acid Anything longer than 60 seconds =

maintaining a manageable, sustainable level of energy production for a sustained amount of time

When you exercise you increase your energy demand so you increase the demand for oxygen and hence increase ventilation and increase cardiac output thus INCREASING OXYGEN DELIVERY

Total capacity to deliver oxygen to tissues is termed

You increase fuel utilisation and increase carbon dioxide production Anaerobic mechanisms produce lactic acid which dissociated into lactate- and H+ which will

the pH

and hence will affect the active sites on enzymes and impede the glycolytic enzymes needed for aerobic energy production

If we initiate sub-maximal exercise, we need 40 L/min to meet metabolic demand

there is a little bit of a lag. There is a rapid rise followed by a steady rise until we match supply with demand

When we finish exercise we continue to breathe at a greater rate because we need to repay the oxygen deb

Some of this energy needed to repay the oxygen debt comes from stored energy - intramuscular ATP, phosphocreatine and

Excess Post-Exercise Oxygen Consumption (EPOC) - this is because you are trying to reverse the metabolic consequences of an oxygen deficit

Ventilatory Response to Exercise:

When exercise begins, breathing rate rapidly increases from around 12 to 20 then it becomes stable for a long time

Reason for ventilation rate becoming stable is increase in

is more efficient at increasing ventilation than increasing respiratory rate

Once the tidal volume starts to plateau, respiratory rate starts to increase

Reason= it is inefficient to increase the tidal volume any more - the tidal volume will never get to the vital capacity because it is energy inefficient to do so

5 challenges of altitude: Hypoxia, thermal stress, solar radiation, hydration and dangerous

Accommodation and acclimatisation:

Accommodation =

response to this kind of stress - this is a rapid physiological change in response to a change in the oxygen environment

Acclimatisation= physiology becomes more efficient so you can get as much out of the air as possible

Low PaO2 stimulates ventilation to increase PAO2 (this increases the diffusion gradient so more oxygen passes into the blood) - this is called

hypoxia

Innate/Developmental Adaptations

Native highlanders have specialised anatomical and physiological adaptations Barrel Chest Larger chest and a bigger set of lungs thus increasing surface area Larger TLC, more alveoli and greater capillarisation This allows more O2 into the body

Increased haematocrit: More RBCs due to the chronic secretion of

This increase the oxygen carrying capacity of the blood

Larger Heart (Right Ventricular Hypertrophy): Pulmonary vasculature

in response to hypoxia

So you need a stronger

side of the heart to push blood through the increased resistance

Increased mitochondrial density- Greater oxygen utilisation

Chronic mountain sickness:

Sometimes these long-term adaptations can be problematic Acclimatised individuals can spontaneously acquire chronic mountain sickness known as

disease. Thought to be due to secondary

in response to hypoxia

RBCs are overproduced to the point where it becomes counter-productive You increase the haematocrit, and as a result, you increase the

This becomes a chronic problem and you continue to produce RBCs There is no interventional medical treatment available - sufferers have to move down to lower altitude

Acute mountain sickness:

High altitude cerebral oedema and high altitude pulmonary oedema are associated with

oxygen environments

This is caused by maladaptation to the high-altitude environment . Impaired ability to coordinate movement-

High Altitude Cerebral Oedema (HACE):

Causes: Rapid ascent or inability to acclimatise

Pathophysiology:

of vessels in response to hyperaemia- more blood going into the capillaries increases fluid leakage

Symptoms: Confusion, ataxia, behavioural changes

Consequences: Irrational behaviour, irreversible neurological damage, death

Treatment: Immediate descent, O2 therapy

High altitude pulmonary oedema:

Causes: Rapid ascent

Pathophysiology:

of pulmonary vessels in response to hypoxia, increased pulmonary pressure, permeability and fluid leakage from capillaries

Fluid accumulates once production exceeds maximum rate of lymph drainage

Symptoms: Dyspnoea, dry cough, bloody sputum

Consequences: Impaired gas exchange

Treatment: Descent, hyperbaric O2 therapy

The alveolar hypoxia in patients with HAPE leads to reflex pulmonary artery vasoconstriction and hence pulmonary artery hypertension and increased capillary leakage

Respiratory failure:

Ineffective ability to exchange gas between the lungs and the blood

There are two main types: Type 1-

respiratory failure

Type 2-

respiratory failure

Type 3: Mixed respiratory failure Combo of type 1 and 2

The main determinants of arterial gas tensions are alveolar ventilation and gas exchange in the lung

Type 1 (hypoxic) - typically a ventilation/perfusion mismatch in the lungs; perfused alveoli are hypoventilated or ventilated alveoli are hypoperfused

Type 2 (hypercapnic) - typically hypoventilated lungs; inadequate gas exchange as alveolar air stagnates and concentration gradients are poor

Notes on renal mechanisms of hydrogen ion regulation:

The kidneys eliminate or replenish H+ from the body by altering plasma

concentration. The excretion of

in the urine increases the plasma H+ concentration just as if a hydrogen ion had been added to the plasma

Similarly, addition of HCO3- to the plasma decreases the plasma hydrogen ion concentration just as if hydrogen ions had been removed from the plasma

When the plasma H+ concentration decreases (alkalosis), the kidneys' homeostatic response is to excrete large quantities of

When acidotic, the kidneys

excrete HCO3- in the urine

Functions of the respiratory tract include:

Gas exchange, host defence, Metabolism of endogenous and exogenous molecules,  Repair and vocalisation

Gas exchange:

oxygenation of the blood and the removal of excess carbon dioxide is the most important function of the respiratory tract

Apart from the special case of the

it is the only organ which can carry out this crucial function.

The need to carry out gas exchange places a number of anatomical and physiological requirements on the respiratory tract:

It must open to the

It requires a mechanism to warm and humidify atmospheric gases

It needs an effective system for gas delivery to the

It must have a large gas-permeable surface

It needs a large

blood supply in close apposition to the gas-permeable surface.

Host defence:

The anatomical and physiological requirements of the gas exchange mean that the respiratory tract is vulnerable to environmental agents. These include organic and inorganic particulates, spores, pollens, fungi, viruses and bacteria.

Protection from these is provided by a combination of physiological and cell biological mechanisms:

Particle

and removal systems in the upper airways.

Resident cells able to produce

able to attack invading organisms.

Migratory cells – macrophages, lymphocytes, neutrophils from the marginated pool “on standby” in the pulmonary vasculature.

Metabolic functions:

The metabolic functions of the lung are performed by specialised epithelial cells and by endothelial cells in the pulmonary capillary network.

As well as the capacity to metabolise many different inhaled compounds, a variety of endogenous substances are metabolised in the respiratory tract or in its specialist blood supply including:

Local hormones: Angiotensin I conversion to

Inflammatory mediators: Bradykinin and prostaglandin degradation

Neurotransmitters: Noradrenaline, serotonin.

Development, growth and repair:

Repair is an important function for all organs, particularly the lung which is open to the

Some insults can be repaired without any evidence of permanent damage

The burden of respiratory disease:

Responsible for

of deaths in the UK

Causes of respiratory disease related deaths:

Cancers of the respiratory system, e.g. lung cancer, pneumonia, Chronic obstructive pulmonary disease (COPD) etc.

Respiratory diseases:

Symptoms

Breathlessness – also known as

a sensation of difficult, laboured or uncomfortable breathing

Causes:  Physiological – strenuous exercise, pregnancy  Psychological – stress, anxiety, panic attack  Pathological – heart disease, lung disease, pulmonary vascular disease, systemic disorders, respiratory muscle weakness

Pathophysiology: Disturbed gas exchange and damaged respiratory

Overview – starts in the nose and nasal passages, then down to pharynx, larynx + trachea, which branches into the primary

which supply the lungs. The lungs sit in the thorax, and are surrounded by

the diaphragm, intercostal muscles and abdominal muscles. All these components are essential for respiration.

Terminology

Airways: air-filled spaces/tubes which take air from the outside to the alveoli.

Alveoli: microscopic spaces lined by very thin simple squamous

through which oxygen + carbon dioxide exchange takes place. Gas exchange takes place within the blood in a network of alveolar capillaries surrounding the alveoli.

Alveolar capillaries: are on the pulmonary circuit bringing deoxygenated blood from the

of the heart via the pulmonary trunk and pulmonary arteries.

Upper airways: comprise the nasal cavities, the nasopharynx (above roof of mouth), laryngopharynx (shared by airway + foodway), and the larynx (voicebox/Adam’s apple – valve that allows air into the lower airways but excludes liquids and solids)

Structural Components:

The Nasal Cavities:

nearly triangular cross-section, with fairly smooth medial and inferior walls but an elaborate lateral wall in which the respiratory epithelium with hairy mucosa covers three scroll-like plates of bones called the

has a complex and important vascular and nerve supply

inspired air passes through these warm and

plates

becoming warmed and humidified on the way and so protecting the lower parts of the respiratory tract from cold shock and drying.

The nasal lining becomes cooled in this process so, during expiration, the nasal lining cools the expired air and also retrieves water by condensation.

Nasal mucus and hairs help exclude a range of airborne particles – because of this the complex, narrow passages of the nasal cavity have a high resistance to

During exercise the nasal resistance to flow means that the

respiratory muscles cannot propel air through the nose fast enough so open-mouth breathing takes over with an increased loss of

and exposure to airborne particles.

Secondary role – sense of smell, also known as

The tract has a specialised epithelium with specialised nerve supply

The Paransal Air Sinuses:

sets of blind-ended out-pocketings (i.e. holes) of the lateral walls of the nasal cavities

The air turnover in these is fairly slow and plays little role in heat and water transfer

Ideas on their functions include reducing the weight of the facial bones, providing a

zone in facial trauma, acting as resonators for the voice, and insulating sensitive structures such as dental roots and eyes from the rapid temperature fluctuations in the nasal cavities.

Infection of the

sinus is common as the opening is high up. All sinuses anterior to the brain have a possible

effect on the brain

Lower airways – comprise the trachea, the bronchi and the

(initially surrounded by smooth muscle but ending as respiratory bronchioles from which alveoli are direct or indirect buds).

The walls of the larynx, trachea and bronchi are held open by plates or crescents of

(a non- mineralised connective tissue, supporting but flexible). The nasal cavities and pharynx are held open by attachments to nearby bones.

The microscopic air spaces (alveoli and bronchioles) contain a surfactant

that prevents collapse caused by surface tension forces.

The Pharynx:

After conditioning of the air, air passes down the back of the nasal cavity to the pharynx, which is the final part of the airway proximal to its separation from the oesophagus

 The pharynx consists of 3 parts:

– posterior to the nasal cavity, and is the Eustachian tube opening

- posterior to the

consists of lymphoid tissue

Laryngopharynx – after the

Food is channelled posteriorly along the oropharynx to the oesophagus

Larynx:

Cartillagenous structure supported from the roof of the mouth by the

bone

Is associated with the lateral

Superior and posterior to the thyroid gland, superior to the

Entire structure is lined by a membrane, which forms a complete sheath on the inside of the

Arytenoid cartilage – attached to vocal ligaments which open and close entry to the

This is crucial – act as a sphincter preventing entry into the lower airways. They are open during inspiration and closed during

when the vocal folds are partially open, and air is passed through, sound is made – this is the mechanism of vocalisation in the mouth

Without the larynx, voice would be

Also, closure of vocal folds increases the pressure in the thorax and abdomen. This can lead to an expulsive force e.g. during sneezing, childbirth + vomiting

Trachea:

Has a regular cartilage arrangement of ~

horseshoe shaped cartilage rings which keep the trachea open

The anterior surface is lined with

Posterior surface consists of

muscle, which is anterior to oesophageal muscle and is needed for

Posterior surface is where cartilage ring is not continuous

The tracheobronchial tree:

Sternal angle at

marks where trachea branches

There is a dimorphism between the primary bronchi, the right side is

and more vertical therefore more things are inhaled into the right lung

The secondary bronchi supply each lung

Within each lobe, tertiary bronchi then supply each pulmonary

With branching of the bronchi, the number of cartilage rings

and the amount of smooth muscle

The lungs and pleura:

The lungs lie within two

separated by a central partition of tissue called the

it contains the trachea, the oesophagus (gullet), the heart and great arteries and veins and various important nerves and lymph vessels)

Each lung and the inside of the pleural cavities are covered by a thin, shiny, moist layer of tissue called the

which allows each lung to slide smoothly within its pleural cavity during breathing.

Each lung has a convex surface facing the ribs- the

surface, a surface moulded to the mediastinum (the

surface) and an inferior (lower or diaphragmatic) surface, which is concave and moulded to the diaphragm, a sheet-like muscle that separates the thoracic and abdominal cavities.

The highest part of each lung, the

, projects 2-3 cm above the clavicle in an adult and really lies in the root of the

Gas exchange occur in the alveoli and alveolar capillaries within the bronchopulmonary segments

Alveoli are air sacs in close proximity to alveolar capillaries, forming a blood-air barrier. The pressure gradient of oxygen drives oxygen across this barrier

PO2 air =

mmHg. PO2 blood =

mmHg

The diaphragm and breathing:

Position of the diaphragm – margin attached to costal margin, centre of dome bulges up because of

difference between the pleural and abdominal cavities. This bulge (and hence the pressure difference) is highest during

Breathing is produced by two main sets of muscles. Contraction of the diaphragm (which is attached to the

, the lower border of the rib cage) pulls the domed centre of the diaphragm down and so

the height of the pleural cavities. Contraction of the

muscles, which almost fill the spaces between adjoining ribs, pulls the ribs upwards towards the relatively fixed first rib; the ribs slope down towards their

ends so the lifting movement of the intercostal muscles increases the depth and width of the

Expansion of the pleural cavities produces a drop in the pleural pressure, so air flows through the airways into the lungs, which expand with the increase in pleural cavity volume.

The lower part of each lung expands downwards to occupy much of the costo-diaphragmatic

(the lowest region of each pleural cavity, which in expiration contains no lung because the margin of the diaphragm is pressed closely against the lower part of the rib cage).

The

nerve (from C3,4 + 5) supplies motor innervation to the diaphragm

There are two components to the chest wall:

Bone + muscle + fibrous tissue and

So we have to think of the chest wall as having the combined properties of both

If you split them up, the rib cage would naturally recoil

The lungs have a tendency to recoil

FUNCTIONAL RESIDUAL CAPACITY (FRC) = when we are at the end of tidal expiration. At the

of that tidal expiration you're at FRC where the rib cage and the lungs are in equilibrium.

The elastic recoil of the lungs inwards and the outward recoil of the rib cage are in

When the two components are in this equilibrium, you need

effort to push the equilibrium in one direction or the other

The pleural cavity (space in between parietal and visceral pleura) is of a

and contains protein-rich pleural fluid

The pleural cavity is at

pressure

When we think about changing pressures, the pleural cavity is going to be the link between the lungs and the chest wall

If we do a full inspiration, we will be expanding the chest wall as well as pulling the diaphragm

So the chest wall needs to pull the lung with it

If the chest wall separates from the lungs, the lungs will deflate - they must move as one

Breaching the Pleural Cavity :

If you get a puncture in the chest wall or lungs, then the fixed volume pleural cavity is compromised

Air will fill the pleural cavity, elastic

will take over and the lung will collapse

If you have a haemothorax then this happens much

Lung Volumes and Capacities

Tidal breathing is usually

Tidal Breathing = the amount of inspiration and expiration that meets

demand

when you're exercising, your tidal volume increases

The end of a tidal breath marks the

Due to the surfactant in the alveoli, you can't empty the lungs fully because you don't want the alveoli to stick together and not reopen

This remaining volume is the

There are 4 main volumes: Tidal Volume Inspiratory Reserve Volume Expiratory Reserve Volume Reserve Volume

Volumes can be combined into capacities:

Total Lung Capacity (TLC) = Everything combined - When you inspire all the way in and fill your lungs up as much as possible, the volume of air in the lungs is the TLC

Capacity (VC) = how much air is within the confines of what we are able to inspire and expire

Functional Residual Capacity (FRC) = the volume of air in the lungs when the outwards recoil of the rib cage and the inward recoil of the lungs are in equilibrium

Inspiratory Capacity = how much extra air you can take in on top of the FRC

Pressures:

Pressures drive flow - without a pressure gradient there would be no flow

NOTE: generally, when we're talking about lung volumes, we use

instead of mm Hg or kPa - this is the default for measuring in respiratory physiology

There are also

pressures- this is the pressure across a tissue or several tissues

There is a

pressure = difference between alveolar and intrapleural pressure

NOTE: you always do the pressure inside MINUS the pressure outside to try and figure out the orientation of the gradient

The

pressure is the important one - it tells us whether there will be airflow into or out of the lung

There are different ways of breathing which involve creating a pressure gradient

You inspire when there is lower pressure inside the lungs - this is

pressure breathing

It is also possible to ventilate using positive pressure breathing This involves increasing the pressure outside by using a ventilator or CPR

Ventilation :

At the start of the cycle there is no

pressure (between alveolar and intrapleural pressure) because there is no volume change

The chest wall expands and creates negative pressure so more air flows in

This establishes a pressure gradient down which air flows

Eventually the pressure gradient will equalise again

Dead Space:

Dead Space = the part of the airways and lung that

participate in gas exchange

The conducting zone is dead space

There could be alveoli that are not perfused or have collapsed within the respiratory zone - this makes up

dead space

Alveolar Dead Space = the parts of the lung that could participate in gas exchange but do not

Physiological Dead Space = Anatomical Dead Space + Alveolar Dead Space

In most healthy individuals, the alveolar dead space is

Normal physiological dead space = 150 mL

Two reversible procedures that can alter a patient's dead space

- cutting off the upper part of the airway so it is no longer dead space

Ventilator - the extra tubing becomes dead space

Ever wanted a longer snorkel?

The snorkel tubing is pretty much extra

Chest-Wall Relationship:

NOTE: diaphragm moves like a syringe - negative pressure makes the air flow Intercostal muscles move up and out - increases the cross-sectional area of the upper chest cavity

It takes relatively little pressure to expand the chest wall to 6L which is relatively easy because the chest wall wants to expand

However, to get the elastic lung to expand, the bigger the volume, the

pressure is needed

So the intact lung has a

shape in terms of its volume-pressure relationship When we exercise, it is inefficient to use the whole of our vital capacity because a lot of energy and effort is expended to utilise the inspiratory and expiratory muscles to the maximum

You want to ventilate the lungs to achieve a higher ventilation performance but you don't want to tire out your muscles

Volume-Time Curve :

Patients are asked to inspire all the way in and then expire all the way out as hard and fast as possible from TLC to RV

Healthy Person - around 75% of the air is out within the first second

Obstructive Lung Disease (e.g. COPD): FEV1 (amount of air forced out of the lungs in 1 second ) would be much lower (can't expel air fast) FET ( the time taken to expel all the air from the lungs) is much higher (takes longer to expel all air) FVC is much lower

Restrictive Lung Disease (e.g. sarcoidosis): FVC is

FEV1 is relatively high - because their conducting airways are quite clear they can expel air relatively easily

Peak expiratory flow:

1. Patient wears nose clip 2.Patient inhales to

3. Patients wrap lips around mouthpiece 4.Patient exhales as hard and fast as possible 5.Exhalation

have to reach RV

Flow-Volume Loops:

1. Patient wears nose clip 2. Patients wrap lips around mouthpiece 3. Patient completes at least one

breath 4.Patient inhales steadily to

5. Patient exhales as fast and hard as possible 6. Exhalation continues until

is reached

7. Patient immediately inhales to TLC 8. Visually inspect performance and time curve

Flow-volume loops combines the other two tests and does almost everything

Inspiration = Downwards Expiration = Upwards

Y axis is the flow rate - the further it deviates from the x-axis, the greater the rate of flow

Examples of Flow-Volume Loops in Lung Disease

Mild Obstructive Disease - the top right line representing the last bit of expiration is usually a

but in people with mild obstructive disease, there is an indentation

The deeper the indentation the more severe the disease

Residual volume is

in obstructive lung disease - because there is air trapped in the alveoli as the small airways linking the alveoli to the outside world have collapsed

TLC might increase

As emphysema degrades the alveolar walls you just get one large alveolus instead of one with several separate segments and hence there is an

in the volume of the lungs

The inspiratory curve is more or less the same

Main changes in obstructive lung disease: INDENTATION of the upper right line (end of expiration) Loop moves to the LEFT

Restrictive Disease:

Flow volume loop is

This is because getting up to a high TLC is difficult because of the restriction to the expansion of the lungs

Because of this, there may be some

in flow rate but it may not be affected

Main changes in restrictive lung disease: Loop is

Loop moves to the

Embryonic development:

The tracheal bud forms from the foregut at

weeks of gestation

By

weeks gestation, bronchial branching is complete o Pulmonary artery branching then follows this

Alveolar development continues until

years of age

Hypoplastic lung – interruption to bronchial branchingdevelopment of small lung with little branching o Isotope ventilation scan will show poor air supply to the lung

Embryogenesis:

Different tissues develop at different rates  Bronchial buds are supplied by systemic vessels

Systemic vessels regress as the pulmonary artery takes over principle supply

The bronchial artery development occurs independently from the

Insult to this development (e.g. infection, vascular accident, trauma) may result in malformation depending on the timing of the insult rather than its nature

Theroretical “insults” to either the dividing bronchus may lead malformations including agenesis (early malfunction), a local lesion (impact to specific area), malformation of systemic supply to “normal” lung or “abnormal” lung, or a malformation in the lung leading to normal pulmonary artery supply to abnormal lung.

Influences on lung development

 Hox genes  Transcription factors  Autocrine and paracrine interactions  Peptide growth factors  Thoracic cage volume  Lung liquid positive pressure  Amniotic fluid volume  Maternal nutrition e.g. vitamin A  E.g. of restricted lung volume: Diaphragmatic hernia (of Bochdalek)hypoplasticity

Airway branching:

with regards to the cartilaginous rings in the trachea and bronchi/bronchioles, the only complete ring is the

in the larynx

With increased branching, there are an increased number of alveoli, ducts, neural network and smooth muscle development. This is to allow the necessary bronchoconstriction and dilation.

There are 25 generations of branching which occurs during pre-natal development.

Pre-natal development consists of 3 development stages: glandular, canalicular and

The development of a foetal airway at

weeks gestation leads to pressure changes in the thorax. This has a trophic effect on development leading to expression of gene which stimulates the branching of the airway

Respiratory “Insult” during maternal pregnancy -

Causes increased respiratory movements and changes in thoracic pressures, while removing some of the soft tissue support and interstitial tissue development

Reduces

of alveoli which leads to reduced support

Reduces airway diameter which leads to reduced support which leads to an infant who is

and more likely to have COPD at an older age

Circulation:

Foetal circulation- Mostly

the lungs