Inflammation/Asthma/COPD Pathophysiology

inflammation

A physiological response to tissue injury and infection caused by biological, chemical, or physical agents

-get rid of cause of injury

-reduce/stop consequences of injury

purposes of inflammation

pain, heat, redness, swelling

cardinal signs of inflammation

acute, chronic

two types of inflammation

1) recognize offending agent

2) recruit leukocytes and plasma proteins

3) activate leukocytes and complement

4) release cytokines and growth factors for damage repair

steps of acute inflammation

1) accumulation of leukocytes

2) activation of clotting, kinin, and complement systems

3) contraction of endothelial cells

blood vessel reaction to inflammatory response

extravasate, phagocytize, release inflammatory mediators, attract macrophages

role of neutrophils in inflammatory response

secrete cytokines (IL-1, IL-6, TNF-a); increase permeability

role of macrophages in inflammatory response

chronic inflammation

continuous exposure to offending agent (antigen) due to pathogen persistence, autoimmunity, or cancer

inflammatory mediators

Ex: histamine, prostaglandins, thromboxane A2, leukotrienes, interleukins, TNF-alpha, interferon gamma

histamine

biogenic amine, synthesized by the body and stored in mast cells and basophils

degranulation

release of histamine from mast cells and basophils due to antigen-antibody interaction

mast cells, basophils

types of cells that store histamine

brain, ECL cells of stomach

non-mast cells that store histamine

Gq

what type of receptor is H1?

Gs

what type of receptor is H2?

brain, smooth muscle, endothelium

location of H1 receptors

brain, gastric mucosa, cardiac muscle mast cells, smooth muscles

location of H2 receptors

H1

histamine receptor that causes:

-increased capillary permeability

-bronchial smooth muscle contraction

-stimulate vagal nerve endings

-modulate circadian rhythm

-itching

H2

histamine receptor that causes:

-gastric acid secretion

-increases sinus rhythm

-inhibition of IgE-induced degranulation

-vasodilation

H1

histamine receptor in which lung effects are primarily mediated (smooth muscle contraction, edema, mucus plugs, wheal and flare response)

cell membrane (phospholipids)

where the arachidonic acid pathway starts

COX

converts arachidonic acid into prostaglandins

5-lipoxygenase

converts arachidonic acid into leukotrienes

prostacyclin, thromboxane A2

two prostaglandins that have effects counteracting eachother

vasodilation, inhibit platelet aggregation

effects of prostacyclin (PGI2)

vasoconstriction, promote platelet aggregation

effects of thromboxane A2 (TXA2)

vasoconstriction, bronchospasm, increased vascular permeability

effects of leukotrienes

COX1

cyclooxygenase that produces housekeeping prostanoids (gastric epithelial cytoprotection, kidney and CV system protection)

TXA2 (Thromboxane A2)

COX 1 is a major source of ____________

constitutive

is COX 1 constitutive or inducible?

COX 2

cyclooxygenase that is a major source of proteinoids in inflammation and cancer; plays a role in BP regulation and maintenance of kidney function

PGI2 (prostacyclin)

COX 2 is a major source of _____________

cytokines

Proteins produced by activated lymphocytes, macrophages, dendritic cells, endothelial, epithelial, and connective tissue cells that mediate and regulate immune and inflammatory reactions

Asthma

Heterogeneous disease characterized by chronic airway inflammation. - defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough, that vary over time, and in intensity, together with variable expiratory airflow limitation

inflammation, airflow obstruction, bronchial hyperresponsiveness, intermittent symptoms

characteristics of asthma

atopy

genetically determined state of hypersensitivity to environmental allergens

eosinophilic, non-eosinophilic, mixed

three main types of asthma

allergic (IgE+), nonallergic

two types of eosinophilic

paucigranulocytic, neutrophilic

two types of non-eosinophilic asthma

IgE

produced by B-cells following exposure to allergen and stimulate Mast cells to release histamine

mast cells, lymphocytes

cells involved in early phase reaction

LTC4, LTB4

secreted by mast cells in early phase reaction, causing bronchoconstriction within minutes

eosinophil, macrophage, neutrophil

cells involved in late phase reaction

IL-4

stimulates eosinophils to release more leukotrienes in late phase reaction

LTC4

produced by eosinophils, macrophages, and neutrophils to cause bronchoconstriction

LTC4, IL-5, IL-13

inflammatory mediators leading to bronchial hyperresponsiveness exacerbations in chronic asthma

histamine, arachidonic acid and metabolites (esp. leukotrienes)

inflammatory mediators in asthma

bronchoconstriction, mucus secretion, edema, microvascular permeability, induction of BHR

effects of leukotrienes in asthma

B2 (sympathetic)

M3 (parasympathetic)

mumoral (histamine, bradykinin, PGs, LTs)

adenosine

factors that control bronchial smooth muscles (constriction/dilation)

cAMP

increased levels cause bronchodilation

stimulate AC

inhibit PDE

methods of increasing levels of cAMP

acetylcholine, adenosine

increased levels cause bronchoconstriction

bronchoconstriction, enhanced mucus secretion, reflex vagal stimulation

role of acetylcholine in asthma

anticholinergic, adenosine antagonist

methods of reducing bronchoconstrictive effects of acetylcholine and adenosine

chronic inflammation;

airway remodeling;

mucus production;

airway smooth muscle;

neural control/neurogenic inflammation

clinical consequences of chronic inflammation

COPD

occurs when airway remodeling becomes irreversible

Th2

according to the hygiene hypothesis, are Th1 or Th2 responses more associated with asthma?

genetic, environment, low birth weight, male gender, atopy

asthma risk factors

allergens/irritants

RTIs

environment

emotions

exercise

cold air

drugs (aspirin)

preservatives (sulfites)

common triggers of asthma

irreversible COX1 and COX2 inhibitor

aspirin MOA

increases production of leukotrienes from arachidonic acid since COX is inhibited

why aspirin is an asthma trigger (AERD - aspirin-exacerbated respiratory distress)

wheezing, dyspnea, chest tightness, coughing

signs and symptoms of asthma

smooth muscle contraction + mucus

cause of wheezing in asthma

muscle effort to overcome airway resistance or hyperinflation from airway obstruction

cause of dyspnea and chest tightness in asthma

airway narrowing, mucus, and hyperresponsiveness

causes of coughing in asthma

EIB (exercise induced bronchospasm)

occurs when pulmonary function measurements in patients with asthma decrease after 6-8 minutes of vigorous exercise

FEV1 (forced expiratory volume in 1 second)

EIB is defined as a drop of 15% or greater in _________ from baseline

nocturnal asthma

Worsening of asthma during sleep due to diurnal patterns of endogenous cortisol secretion and circulating epinephrine

low cortisol levels (anti-inflammatory steroid)

reason for nocturnal asthma and is worst at approximately 3AM

asthma exacerbations

An acute event characterized by a worsening of the patient's respiratory symptoms that is beyond the normal day-to-day variations and leads to a change in medications; Worsening shortness of breath, cough, wheezing, and chest tightness, or some combination of these symptoms

COPD

Common preventable and treatable disease characterized by persistent airflow limitation (that is not fully reversible) that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and lung to noxious particles or gases

chronic bronchitis, emphysema

COPD is typically described as either ________________ or ________________

tomacco smoke

main exposure risk factor for developing COPD

AAT deficiency

main genetic predisposition that puts patient at risk for developing COPD

elastin

protein that keeps airways open during expiration

1) recoil (respiratory system goes back to normal size with expiration)

2) keep alveoli open during expiration

functions of elastin

elastase

enzyme that breaks down elastin and is inhibited by AAT (alpha-1 antitrypsin)

AAT

inhibits elastase activity in the airways, allowing for normal lung function

elastin breakdown (elastase)

AAT deficiency increases ____________________ which leads to airway obstruction

1) decreased recoil (air trapping)

2) collapse of alveoli

effects of having high levels of elastase (increased breakdown of elastin)

emphysema

disease of parenchymal destruction due to increased levels of proteases (elastase) and destruction of alveolar wall and capillary bed

air trapping, gas exchange

in emphysema, increased elastase results in _______________ and destruction of alveolar wall and capillary bed results in reduced _______________

bronchitis

disease of small airway in which there is increased mucus production and very limited airflow and alveolar perfusion

dyspnea, chronic cough, sputum production

cardinal signs of COPD

barrel-shaped chest, pinkish complexion while breathing (pink puffer)

presentation of emphysema

cyanotic (blue bloater)

presentation of bronchiolitis

neutrophils, large increase in macrophages, CD8 T-cells

cells involved in COPD

eosinophils, small increase in macrophages, CD4 T-cells, mast cells

cells involved in asthma

parenchymal destruction

main consequence of COPD specifically

fragile epithelium and thickened basement membrane

consequences of asthma specifically