Pulmonary defense mechanisms

PULMONARY DEFENSE MECHANISMS

Dr. Dalia Abdallah El-ShafeiLecturer, Community medicine department, Zagazig

University

PARTICLES

Inhalable particles are small droplets or solids -

organic or inorganic, viable or nonviable- that

can become airborne and penetrate into the

oral or nasal airways.

FACTORS AFFECTING PARTICLES’

EFFECTS:

Diameter

Shape

Density

Composition

Concentration

Dimensions of Air passages

Pattern of air flow

DIAMETER

Spherical particles:

Mass median diameter (depend on physical

diameter & density)

Non-spherical particles:

Aerodynamic diameter (depend on

aerodynamic drag)

A particle falling through the air under the force of gravity

(gravitational sedimentation) accelerates until it reaches a

velocity at which the force of gravity is just balanced by the

viscous resistive force exerted by the air (Stokes' law). This

velocity is known as the terminal settling velocity.

Thus, the aerodynamic diameter of a particle, however shaped,

is taken as the diameter of a unit density sphere that would

have the identical terminal settling (Stokes) velocity.

AERODYNAMIC DIAMETER

AEROSOL SIZE DEFINITION

Inhalable

• >100µm

Thoracic

• >10µm

Respirable

• >5µm

EPA PARTICULATE MATTER (PM)

Total PM

TPM

(Supercoarse)

>10µm

Coarse PM

PM10

2.5-10µm

Fine PM

PM2.5

•1-2.5µm

Ultrafine PM

<1µm

SHAPE

Fibrous

(length : diameter) = (3:1)

PATTERN OF AIR FLOW

Slow deep breathing:

↑ sedimentation in all RT.

Rapid shallow breathing:

↑ impaction in LAWs (mainly in “hot spot”

around bifurcation angle) & sedimentation in

SAWs.

PARTICLES DEPOSITION PROCESSES

Perfect Lung

Mechanisms of deposition of aerosol

IMPACTION

Particles with sufficient mass will strike withresp.epith.surface at points of branching andcurvature “Hot spots”

As direction of air velocity change, particles’inertial force will prevent them fromchanging directions at rate as that of air flow.

The greater the mass, the less ability ofparticles to change direction with air flow.

SEDIMENTATION

Particles which are of sufficiently small size to

escape deposition by inertia, may deposit on

resp.epith. Through sedimentation when velocity

of air flow become slow.

Gravity is the predominant force.

Sedimentation rate α particle density.

Sedimentation rate α (particle diameter)²

DIFFUSION

For extremely small particles “Brownian

motion” in which suspended particles

bombarded by surrounding gaseous

molecules.

Rate of diffusion inversely proportionate to

particle diameter.

LUNG DEFENSE MECHANISMS

Upper airway filter

Lower airway filter

Macrophage clearance to

airways

Macrophageclearance via lymphatics

UPPER AIRWAY FILTER

Hairs & mucosal folds over turbinate direct

airflow through nose so most particles > 15 µm

diameter, hit surface and carried in mucus to

pharynx then swallowed.

If particles are irritant or allergic→ running

eyes &nose + sneezing.

At work a certain tolerance may develop.

Heavy work or nasal obstruction → mouth

breath → bypass UAW filter

LOWER AIRWAY FILTER

Mucociliary epithelial lining (goblet cells,

submucosal seromucus glands) act as a low

resistance filter, which remove nearly all

particles down to 5 µm.

Particles carried in the mucus (viscoelastic)

back to larynx, joining particles from UAW.

200 cilia per cell, each beat 1000 times/min in

a wave-like pattern.

Mucociliary escalator

Goblet Cell

Ciliary action

Cilia just touching the gel layer

Gel layer of the mucus above the sol layer

Irritants → + nerve endings

→ Cough + Airway

narrowing + Outpouring of

secretions. → prolonged

exposure → goblet cell

proliferation + submucosal

gland hypertrophy →

Chronic bronchitis.

Normal airway (above); Enlarged mucous glands (below)

IMPAIRMENT OF NORMAL MUCOCILIARY

FUNCTION

Mucus: too much, or change in composition, e.g.

chronic bronchitis, cystic fibrosis, asthma

Cilia: paralysis by toxic gases

bronchial epithelium destroyed

congenital defect of ciliary motion

MACROPHAGE CLEARANCE TO AIRWAYS

Particles getting beyond mucociliary clearancecalled “Respirable or Alveolar dust”

Very small particles (<0.5 µm) sediment so slowly→ + type II cells → surfactant → coat particles.

Macrophages move out from wall →engulf coatedparticles → some moving back in when fullyloaded →many of dust particles dissolve bylysosomal enzymes → when they are fully ladenwith insoluble material →migrate throughinterstitium to centers of lobules →enter mucus-lined airways →carried by mucus to larynx withrest of dust.

By this mechanisms, lungs can clear most

retained dusts as results of regular exposure

at work up to 4mg/m³ of respirable particles

provided that macrophages not damaged.

Above this level →system become

overloaded →dust accumulate in lung

IMPAIRMENT OF NORMAL MACROPHAGE

FUNCTION

Inhaled gases (ozone, cigarette smoke)

Toxic particles (silica)

Alveolar hypoxia

Radiation

Corticosteroids

Alcohol ingestion

ALVEOLAR MACROPHAGE

Alveolar macrophage in the corner of an alveolus

MACROPHAGE CLEARANCE VIA LYMPHATICS

Failure of dust clearance usually a result ofcombination of dust (overload + property) →damage macrophages → cell die → dustpicked up by other macrophages whichattempt to carry it to Hilar LNs via lymphatics(inter lobular septa & under pleura)

Dust can get struck along either route or inhilar LNs

Some carried on into blood stream to spleen,BM, or kupffer cells in liver, and soaccumulate in body.

Clearance of deposited particles

LUNG IMMUNE DEFENSES AGAINST

ENVIRONMENTAL AGENTS

PATHOGENS

Pathogens enter the airways from two major

sources:

Inhalation of bioaerosols in the environment

Aspiration of nasopharyngeal secretions.

AntimicrobialComponents

Lysozyme & Lactoferrin

SLPI

surfactant

Antibodies & Complement

IgA,IgG

Antioxidants

Immune cells

ANTIMICROBIAL COMPONENTS

Two of the most abundant antimicrobial

proteins of airway secretions are:

Lysozyme & Lactoferrin (0.1 - 1 mg/ml).

Secretory leukoprotease inhibitor (SLPI)

surfactant

Lysozyme:

- Enzymatic lysis of bacterial cell walls, can also kill

bacteria non-enzymatically.

- Highly active against many Gram +ve species but

is relatively ineffective against Gram -ve bacteria.

- Produced by both epithelial cells & leukocytes.

- It is about 10-fold more abundant in the initial

"airway" aliquot than in later samples of BAL.

Lactoferrin:

- Iron-binding protein highly abundant in the specific

granules of human neutrophils & epithelial

secretions.

- Inhibits microbial respiration & growth, by

sequestering essential iron.

- Can also be directly microbicidal.

Secretory leukoprotease inhibitor (SLPI)

- Antimicrobial activity against in vitro Gram - ve

& +ve bacteria.

Surfactant

- At the alveolar level, there are 2 components of the

surfactant layer: Surfactant proteins A & D.

- Bind to microorganisms & enhance adhesion &

phagocytosis of microorganisms by agglutination

& opsonization.

- Also directly antimicrobial.

ANTIBODIES AND COMPLEMENT

Potent immune system molecules present in airway& alveolar lining fluid.

Mainly immunoglobulin A (IgA) & G (IgG).

IgA “UAW” is predominantly found along the nasopharyngeal mucosa & in large airway; its

relative concentration decreases progressively from larger to smaller airways.

IgG “LAW” is the major antibody found in alveolar fluid.

ANTIOXIDANTS

The first line of defense against inhaled oxidant

gases (& particles) “O3 & NO2”, normally present

in lung lining fluid.

Glutathione & Ascorbate, Uric acid, & α-

tocopherol.

Achieving toxicity through intermediates formed

when antioxidant defenses are overwhelmed.

SURVEILLANCE BY CELLULAR FIRST

RESPONDERS

Macrophages

Include subsets in distinct anatomic compartments(Alveolar, interstitial, & airway macrophages).

The most numerous & well studied is alveolarmacrophage (AM). Normal adult lungs contain about20*109 Ams (BAL routinely yields 10 to 20*106 ).

AMs are ultimately derived from BM hematopoiesis.

Injury → influx & differentiation of blood monocytes→ Increases in macrophage number.

Life span of AMs in normal individuals range fromone to several months.

The main function of the AM is phagocytosis &

clearance of inhaled material.

The AMs can ingest, but fail to kill, certain

microorganisms, as (Mycobacterium, Nocardia &

Legionella) which are then capable of replicating

intracellularly. Ultimate eradication of these

pathogens requires the development of CMI.

The process of phagocytosis:

1- Recognition or binding of phagocytic targets.

- AMs possess a broad array of membrane

receptors that mediate binding of organisms and

particles.

- Phagocytosis is initiated by these specific

receptors that either recognize serum components

(opsonins) (opsonin-dependent) or directly

recognize molecular determinants on the

target(opsonin-independent).

2- Internalization & killing:

AM has considerable microbicidal machinery.

Generates Reactive Oxygen Species (ROS)

(using the "respiratory burst") that contribute to

pathogen killing.

Reactive Nitrogen Intermediates (RNI) can also

contribute to pathogen killing.

3- Movement of AMs to the Mucociliary escalator:

After ingestion of particles, AM functions

ultimately to remove offending material from lung.

Movement of AMs to the mucociliary escalator &

clearance to the oropharynx.

Entry of macrophages into tissue compartments,

lymphatics & migration to thoracic lymph nodes.

4- Release of inflammatory mediators

Include lipid mediators (e.g., LTB4) &

chemokines (interleukin-8).

AM recruit additional help {polymorphonuclear

neutrophils (PMNs)}.

Ciliated Epithelial Cells

Integral part of the mucociliary clearance system.

Produce important components of the lining fluid inairway & alveolus {Mucus, Surfactant,Complement, Lysozyme}.

Some direct antibacterial function.

Secrete a large array of cytokines & othermolecules (e.g., IL-1, -5, -6, -8, GM-CSF) whichchemoattract & activate cells of the innate &adaptive immune system, which, in turn,immobilize and kill microorganisms.

Polymorphonuclear Neutrophils

- The major 2nd cellular defense.

- Up to 40% of blood PMNs are marginated or intransit through the lung, facilitating recruitment whenneeded.

- Rapid & large movement of PMNs into the alveoli isachieved by influence of several chemotactic factorsreleased by AMs & other lung cells (e.g., IL-8,leukotrienes, complement fragments).

- Killing of ingested microorganisms by generation ofNADPH oxidase-dependent ROS (e.g., superoxide,hydrogen peroxide) & by phagolysosomal fusion.

Mast Cells

In intraepithelial locations or around blood vessels

& bronchioles.

Produce Tumor Necrosis Factor (TNF) & a wide

range of cytokines & chemokines & important lipid

mediators, such as LTC4 and LTB4.

Natural Killer Cells (NK)

Arise from same hematopoietic lineage as T cells, (Butnot mature in thymus & not express re-arrangedantigen receptors).

Important in initial defenses against viral infection oflungs. Local release of IL-12 & IL-15 by dendriticcells & macrophages contributes to stimulation of NKcells.

Recognize virus-infected (& neoplastic) cells becauseof their altered expression of leukocyte antigen (HLA)class I tissue antigens.

Release Interferon-γ (IFN- γ), which, in turn, leads torecruitment of other immune cells.

Dendritic Cells (DCs)

Characteristic long, branched processes. In airways,

alveolar parenchyma, and thoracic lymph nodes.

Specialized mononuclear phagocytes with important

functions in antigen presentation & initiation of adaptive

immune responses.

Acting as sentinels in airways, they sample incomingpathogens and antigens through by phagocytosis.When this is accompanied by a second, "danger"signal, they undergo a phenotypic & functional changefrom their basal immature state.

This maturation promotes the processing of antigenand its presentation on the cell surface and themigration of the dendritic cell to T-cell rich areas ofnearby lymph nodes. Here they can initiate or amplifyadaptive immune responses by triggering proliferationand activation of antigen-specific T lymphocytes.

CYTOKINES

Critical for successful orchestration of defense

mechanisms against environmental agents & are

also mediators of untoward outcomes such as

acute injury & chronic inflammation & fibrosis.

TNF & chemokines which function in both acute

and chronic phases of these processes.

Tumor Necrosis Factor

TNF- αis a protein.

Monocytes express at least 5 different molecular forms of TNF-α.

Macrophages are considered the most prolific sources.

lymphoid cells, mast cells, endothelial cells, fibroblasts, and neuronal tissue.

Two types of TNF receptors, TNF-R1 & TNF-R2, are present on virtually all cells except RBCs.

Present during acute response to acute inflammatory responses to toxic environmental agents{silica, asbestos, air pollution particles,

welding fumes, ozone}.

Chemokines

Plays a critical role in this process of recruitment

& maintenance of inflammatory cells in the lungs

after environmental exposures.

Produced by Ams, monocytes, neutrophils, T & B

lymphocytes, NK cells, epithelial cells,

fibroblasts, smooth muscle cells, mesothelial

cells, and endothelial cells.

ADAPTIVE IMMUNITY

The adaptive immune response to pulmonary

pathogens includes (humoral & cellular components).

Both B & T lymphocytes are present in normal lung.

B cells are predominantly found in airway lymphoid

aggregates, where they outnumber the T cells.

In normal lavage samples, approximately 5-10% of

cells are lymphocytes, which, in turn, can be further

divided into functionally important subsets, for

example, CD4+ T helpers & CD8+ cytotoxic T cells.

GRANULOMATOUS INFLAMMATION

In response to certain infectious agents & persistentforeign material, & as part of a disease of unknownetiology (e.g., sarcoidosis).

Chronic inflammation, dominated by mononuclearphagocytes “macrophages, epithelioid cells, &multinucleated giant cells”.

Typically, these cells congregate & form well-demarcated focal lesions called granulomas.

Admixture of other cells,(lymphocytes, plasma cells,& fibroblasts).

Granuloma formation typically ends in fibrosis.Fibrosis serves to wall off the granuloma contents andlimit spread of infection and organ damage.