Basic Mechanisms

Role of Inflammation
Charles E. Reed, M.D.
,

of Asthma

F. C. C.P.

It

is

now

recognized in asthma

that

the

basic airway

reason

for

airway The

obstruction

is chronic

inflammation.

and bronchospasm are, in part at least, a consequence of the inflammation. Optimum patient care needs to focus on preventing inflammation when possible and using anti-inflammatory drugs when prevenhyperresponsiveness

tion is not possible. When chronic asthma is mild, aerosol gI ucocorticoids or cromolyn suffice. Acute exacerbations that do not respond fully to bronchodilator drugs usually should be treated by a course of oral glucocorticoids. A few patients with severe disease require oral glucocorticoid therapy indefinitely.

ifective

treatment requires of the

of an both disease

individual

patient

with of the of the

mucosal quamating tegrate individual

inflammation eosinophilic all of these patients.

ANATOMIC

of a special bronchitis. definitions

kind,

chronic can them

desinto

asthma pathogenesis outcome patients. important clinical outcome patient variety

an understanding and a knowledge

Clinicians and apply

of therapeutic Understanding because, trials ofa may provide selected respond

trials conducted the pathogenesis by the nature of conclusions group differently More ofpatients. from the the about

in a series of is especially their design, the Any average severity average particular for a and patient treat,

BASIS

OF

OBSTRUCTION

There bronchospasm acute

are changes

two

main and

components inflammation. caliber, can

of the

obstruction: by

Bronchospasm, be recognized

in airway

of reasons.

importantly,

pathogenesis from time asthma Study the

of the disease varies in the same to time. Ofall the diseases physicians

abrupt changes irritant fumes bronchodilatation. recognized histamine,

in symptoms on exposure to allergens, or dusts, or changes in FEy, after Airway hyperresponsiveness can be tests with exercise, inflammation cold air, can in Airway

may have the ofthe pathogenesis

most complex pathogenesis. has been hampered because This known and

by provocation or methacholine.

definition

controversy

of asthma has been controversial. arises because the cause is not may not be a single cause), definitions are, therefore, need a definition that Usually answers

be recognized by increased blood or sputum, by bits in sputum

numbers of eosinophils of desquamated epithelium of immediate but instead days.

(indeed,
operational demiologists

there

necessary. Epican be applied in a on

response
slow

(creola bodies), and by lack of the FEy, to bronchodilators, to glucocorticoids over

response

several

large scale surveys. definition relies on questionnaire. variability Pathologists tion have and have

such an epidemiologic to specific items on use of a definition airflow less say based obstruction. in the definibut autopsies about the inImmu-

Histopathology Histopathology cosa is infiltrated eosinophils, and hum is particularly is infiltrated lymphocytes, completely membrane inflammation epithelium pecially shows typical changes. The submuand epitheand the cells, esin places a bare deposiare increase glands, exudate ciliated
1988

Physiologists reversibility had relatively

with lymphocytes, monocytes, blood vessels are dilated. The damaged, cilia absent, with inflammatory and is vacuolated and sloughed thickened and off leaving by collagen desquamation

because biopsies are contributed essential component allergists allergic mechanisms

not feasible, information the have

flammatory nologists and IgE-mediated deal caliber,

*professor

of airway studying asthma

obstruction.

pathogenesis of learned a good changes and in airway bronchial

has

been basement tion. uniform mucosal smooth excess Damage This

about

the airway

of acute

not in and and es175

hyperresponsiveness,

in Internal Minnesota.
Reprint 55905

of Internal Medicine
Dr

Medicine, Mayo Medical School; Consultant and Allergic Disease, Mayo Clinic, Rochester,
Reed, Mayo Clinic, Rochester, Minnesota

but are patchy. There is also goblet cells, bronchial mucus muscle. Because of inflammatory mucus of the secretion epithelium there with
CHEST

requests:

is increased loss of the

sputum.

I 94 I 1 I JULY,

calator

contributes

to mucus
DESQUAMATION

stasis and mucus

AND EoSINoPHIu

plugs.

late appear

upon

stimulation in tissues low

of

the

IgE type. type.

receptors. lavage There factor

Most fluids is some

eosinophils
EPITHELIAL

and bronchoalveolar density

to be of the

What

is the basis for the shedding

ofthe

epithelium?

evidence eosinophils

that an endothelial-derived to the low density

can change

Gleich and colleagues2 have uncovered considerable evidence that it is the immediate result of toxic
proteins major evidence of eosinophil extracellular

from eosinophil basic protein and

is as follows: accumulation

granules, eosinophil

particularly peroxidase. occur

the The at sites

BRONCHIAL

HYPERRESPONSIVENESS

AND

INFLAMMATION

first,

the lesions

ophil
tients

major admitted protein

and especially at sites of deposition of large amounts of the eosmbasic protein. Second, sputum from pafor treatment ofasthma contains major at a concentration of 1 to 100 pg/ml. concentration than major in basic is much expectorate protein added higher sputum. at the And

basic site

Bronchial hyperresponsiveness, a feature characteristic of asthma, is linked to inflammation. Epithelial damage by ozone enhances bronchial response to provocation tests.6 Cartier et al found that patients who had a late response to allergen inhalation had increased bronchial response to histamine that in some cases lasted several days.7 The late phase is associated with eosinophils and eosinophilic granular proteins in bronchoalveolar lavage fluid (see below). It is, therefore, of considerable significance that in vitro studies show that stripping epithelim away from airway enhances bronchoconstriction. There is a factor from
normal epithelium that relaxes bronchial smooth muscle.8 Incubating excised bronchial tissue with MBP at concentrations found in sputum of asthmatic patients similarly enhances bronchial contractility (NA Flana-

Doubtless,

the

of deposition

third, purified

to explants

of guinea pig trachea damages cilia in low concentrations and causes epithelial desquamation at concentrations major
damage Also, of the

of

10
many

to

100

pg/ml.

These

concentrations in vitro

of

basic protein

also kill shistosomules

and

kinds

ofmammalian

tissue culture

cells.

eosinophil

major

lesions

in many

basic protein occurs at the site other diseases associated with

eosinophilia. Eosinophilia Logically, ophils

steps:

han,

GJ Gleich,

personal and Late

communication). Phase is by
asthma

this

damage a sequence

by toxic of eosinophil

proteins growth

from three in

eosindiscrete bone

inflammation Although
patients with

Allergic no more about

Reaction means intense airway limited eosinoinflamto with

involves

of at least

eosinophilia
allergic

1) stimulation

(indeed,

patients

marrow; 2) localization by chemotactic factors; Information and growth There are philic
about

of eosinophils in the bronchi and 3) degranulation in situ.3

nonallergic phiia), mation nisms.

interest

asthma much of what

may

have

is known

factors several

eosinophilcolony stimulating factors from lymphocytes is accumulating candidates for the specific eosinofactor including peptides and pro-

comes from study of IgE-mediated mechaIn the past 20 years there has been growing in the late phase of immediate hypersensiAfter

chemotactic

tivity
stricture

inhalation test there that

of

allergen

in

a bronchial

teins,

leukotriene

B4, and

platelet

activating

factor,
Many of Though of IgE

provocation subsides.

but as yet their roles have not been defined. them attract neutrophils as well as eosinophils. at times reactions sporadically bered stimuli
asthma

reaction

is an immediate bronchoconlasts for 30 to 60 minutes and a second wave of obstruc-

In some

patients,

neutrophils in

are found

in the late phase

the nose and bronchi in the lesions, neutrophils Similarly,

and do occur are far outnumthere are several their role in eosinophils by their subjects from have a subjects The in-

tion develops that peaks at four to 12 hours. Occasionally, nocturnal asthma recurs for several days, probably another reflection ofairway hyperresponsiveness. Similar late responses occur in the skin and nose. IgE antibody is both necessary the late phase to nonallergic assumed that IgE antibody affinity the initial occurs and sufficient to transfer recipients. It is generally

by

eosinophils.

for eosinophil has not been into

degranulation, but clarified. Circulating at least two

can be divided density. Circulating have a density subjects

density

categories

eosinophils from normal of about 1.088. Eosinophils hypereosinophilic The eosinophils into these two appear syndrome ofasthmatic populations.

reaction between allergen and with antibody bound to high cell

initiates

receptors

in mast

membranes.
a chain

Bridging
of biochemical

of

with

the

of 1.078.

two antibody molecules reactions that results mediators. probably lumen The takes initial place

in release allergen on mast situated

of histamine IgE cells between reaction lying

and other in asthma free in the cells.

are
type.4

distributed numbers

creased are more

to be mainly

the low density granules, and are

These low density cells have smaller more easily stimulated to degranulate, toxic

and on others

epithelial

receptors,

to worms. They have more low affinity IgE and only low-density eosinophils degranu-

Both in rodents and in man, neous with two major types, tissue. These
types differ not

mast cells are heterogemucosal and connective

only in their distribution,

176

Symposium

but 48/80,

also in their to various

morphology non-IgE of both

staining stimuli the

characteristics, and

cockroaches, mation.
gens,

are

frequent

causes

of allergic of relevant

inflamaller-

response

such as compound proteoglycans used nasal

After
patients

and character enzymes of the Naclerio

specific should

identification

make

every

reasonable

effirt

to

and co-workers#{176} have

challenge

avoid them. This nents-demonstration or in vitro symptoms

tests,

identification of IgE

involves antibody

three compoby skin tests exists in of

as a model of the allergic reaction. During the immediate response to ragweed mast cell mediators, histamine, prostaglandin D2 (PGD2), and tryptase appear in the nasal washings. During the late phase, these same mediators reappear, except PGD2. Inasmuch as

knowledge
exposure.

that the allergen

the air in the patients with

environment,

and correlation

In choosing drug therapy, attention voted to controlling the inflammation.

PGD2 is a mediator produced basophils, and as glucocorticoids

ator phase,
recruited

only by mast cells, not do not inhibit medido so in basophils,

in preventing

release

in mast
are

cells
effective

but

and

should be deIn acute, severe asthma, systemic glucocorticoids are the only effective anti-inflammatory therapy and are almost always mdicated. In chronic asthma, aerosol cromolyn or aerosol glucocorticoids require continuous Episodes of asthma often
zation

gl ucocorticoids
Nacleno
into

and colleagues the arena Neutrophils

suggest and washings

granule

the late that basophils mediators also hours

also

are the source

ofthe

usually suffice, but severe cases therapy with oral preparations. both in children and adults are viral infections. is not due The associated colonito bacterial

in the

late

phase.

eosinophils at four
proteins

provoked

by

begin to appear in the nasal and increase later. Eosinophil

bronchial

inflammation

appear during the late phase indicating that eosinophils have been stimulated to release their toxic proteins. Similarly, first neutrophils lavage and then fluids eosinophils peak appear in the
in bronchoalveolar

and does not respond to antibiotics. sode is severe, a course oforal prednisone
ate, as it is during an exacerbation
REFERENCES
1 Naylor

If the epiis appropri-

from

any cause.

during

the late phase

obstruction

of the asthmatic response. Eosinophils circulation at 24 hours at a time the airway has passed. It is not yet known how long persist after an antigen challenge, but in

eosinophils some cases

peripheral
peripheral

blood
blood

eosinophilia
eosinophilia

lasts at least a week.

correlates temporally

The

with the hyperresponsiveness. Like eosinophils, some lung macrophages lymphocytes these cells have low affinity play in generating IgE receptors. the

and some The role of

inflammation

asthma remains to be defined, lymphocytes in the bronchial

but the prominence of wall strongly suggests

they are important.

CLINICAL IMPLICATIONS

6 information? by to
7

What

use can the clinician

make

ofthis

How does it affect patient changing focus of treatment inflammation.

management? Mainly from bronchospasm

B. The shedding of the mucosa of the bronchial tree in asthma. Thorax 1962; 17:69-71 GleIch CJ, Motojima 5, Frlgas E, Kephart GM, Fujisawa T, Kravis LP The eoslnophiic leukocyte and the pathology of fatal bronchial asthma: evidence for pathologic heterogeneIty. J Allergy Clinc Immunol 1987; 80:412-15 Slifman NR, Adolphson CR, Cleich GJ. Eosinophils: biochemical and cellular aspects. In: Middleton et al, eds. Allergy principles and practice, 3rd ed St. Louis: CV Mosby (In press) Fukuda T, Dunnette SL, Reed CE, Ackerman SJ, Peters MS, Gleich GJ. Increased numbers of hypodense eosinophlls In the blood of patients with bronchial asthma. Am Rev Respir Dis 1985; 132:981-85 Rothenberg ME, Owen WFJ, Silberstein DS, Soberman RJ, Austin KF, Stevens RI. Eosinophils cocultured with endothelial cells have Increased survival and functional pmpertles Science 1987; 237:645-46 Golden JA, Nadel JA, Bouchey HA. Bronchial hyperfrrltability in healthy subjects after exposure to ozone. Am Rev Respir Dis 1978; 118:257-89 Cartier A, Thompson NC, Firth PA, Roberts B, Tech M, Hargreave FE. Allergen Induced Increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and

Prevention
way sure accounts

of exposure
for as much

to allergens
as 5 percent

is an effective
expocases. airway ofasthma

of preventing

inflammation.

Occupational

change in airway caliber. J Allergy Clin Immunol 1982; 70:170-75 8 Flavahan NA, Aarhus LL, Rimeile TJ, Vanhoutte PM. Respiratory epithellum Inhibits bronchial smooth muscle tone. J AppI
Physiol and 1985; 98:834-38

Longitudinal
red cedar

studies
or toluene

of workers
diisocyanate

exposed
reveal

to western
that

9 Befers AD,

Blenenstock
New

J, Denburg
York: Raven

JA. Mast cell differentiation

Press, 1986

obstruction can persist months and years after exposure ceases. Airway hyperresponsiveness persists even longer. The severity and persistence of asthma increases as exposure studies have not yet to extrapolate this asthma
young

heterogeneity.

been done, information

Although prospective it seems reasonable about occupational In children and

to environmental

allergens.

adults,
and

airborne
molds and

allergens,
indoors

both
like

outdoors
pets,

like
and

pollens

mites,

10 Naclerlo RM, Prood D, lbgia AG, Adklnson NF Jr, Meyers DA, Kagey-Sobotka A, et al Inflammatory mediators in late antigeninduced rhinitis. N EngI J Med 1985; 313:65-8 11 Wardlow AJ, Dunnette S, Gleich CJ, Collins J% Kay AB. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactlvity. Am Rev Respir Dis 1988; 137:62-9 12 Chan-Yeung M, MacLean L, Paggioro PL. Followup study of 232 patients with occupational asthma caused by western red cedar. (Thuja plicata)J Mlergy Clin Immunol 1987; 79:792-96

CHEST

94

I 1 I

JULY, 1988

177