The Pulmonary Circulation in Health and Disease

552 Pages·1987·22.519 MB·English

by  James Will (Eds.)

The Pulmonary Circulation
in Health and Disease
Edited by
James A. Will
Department of Anesthesiology
Medical School and Department of Veterinary Science
College of Agricultural and Life Sciences
University of Wisconsin
Madison, Wisconsin
Christopher A. Dawson
Department of Physiology
Medical College of Wisconsin
Milwaukee, Wisconsin
E. Kenneth Weir
Cardiovascular Section
Veterans Administration Medical Center and Department of Medicine
University of Minnesota Medical School
Minneapolis, Minnesota
Carl K. Buckner
School of Pharmacy
Division of Pharmacology and Toxicology
University of Wisconsin
Madison, Wisconsin
1987
ACADEMIC PRESS, INC.
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Preface
Most previous symposia have addressed particular aspects of the
pulmonary circulation, such as specific disease entities (primary pulmonary
hypertension, hypoxic pulmonary vasoconstriction) or the role of a particular
mediator or ion. It was the intent of this symposium to bring together an
interdisciplinary group of acknowledged experts in order to create a more complete
picture of the pulmonary circulation under normal and diseased conditions. We
chose to include various aspects of the physiology (including hemodynamics and
endothelial function), morphology, and pharmacology of the lung on which to
base further presentations. Included are specific discussions on the relationship
between gas exchange and blood flow through the lung, the mechanisms of
pulmonary hypertension, and causes of clinical pulmonary hypertension (including
epidemiology, management of pulmonary thromboembolism, and exogenous
influences).
This book is primarily directed to basic scientists studying the lung, and
clinicians such as cardiologists and pulmonologists. It should also be of interest
to anyone confronted with the effects of alterations in lung function. It is clear
that changes in the lung can affect virtually every other organ system whether
directly or through complex interactions. Knowledge of the pulmonary circulation
and these interactions is scattered and unfocused. We hope that this book will pull
together and clarify the role of this secondary circulation.
JAMES A. WILL
CHRISTOPHER A. DAWSON
E. KENNETH WEIR
CARL K. BUCKNER
ix
Acknowledgments
A symposium and a book like this cannot occur without the help and
cooperation of the organizing committee and every speaker and chairman. The
presentations by these participants were outstanding and I'm certain that you will
find their chapters concise and informative. I am deeply indebted to all of these
people who made this venture a success. My only regrets are that we had to
disappoint some people and could not extend offers to them to present invited
lectures. I apologize to those who feel left out; I am certain their contributions
would have been valuable additions. I consider it a privilege to have been the
director of this program. I hope that our time for programs focusing on the
interdisciplinary aspects of the pulmonary circulation is not past and that we may
bring together an equally dedicated group in the future.
I want to thank my family for being patient with me as I agonized over
the difficulties in pulling together the financial support. It is relevant at this time
to thank all of the contributors, who generously supported the symposium; the
pharmaceutical companies; the Graduate and Medical Schools of the University of
Wisconsin, who provided the seed funding; the Department of Anesthesiology of
the Medical School, who understood my problems and cooperated to help whenever
necessary; my secretaries, program assistant, and student employees, who helped
whenever things got out of hand; and the Anesthesiology Department of the
Medical College of Wisconsin, which stood by to help me financially if needed.
Without these friends, we could not have reached our goals.
Finally, I want to thank my daughter, Lorna, whose expertise in editing
and producing these chapters on a Macintosh computer contributed to the ultimate
success of this volume.
J. A. WILL
xi
xii Acknowledgments
The financial supporters of this symposium and book are listed below in
alphabetical order:
Anaquest
Burroughs Wellcome Fund
The Council for Tobacco Research, Inc.-USA
Glaxo, Inc.
ICI Americas
Key Pharmaceuticals, Inc.
McNeil Pharmaceutical
Roerer Group, Inc.
Roerig
Smith, Kline and Beckman
The University of Wisconsin Graduate School
The University of Wisconsin Medical School
The Upjohn Company
Wyeth Laboratories, Inc.
EDITOR'S NOTE
The organizing committee and editors of this book
wish to express special thanks to the Journal of
Critical Care (Grune & Stratton, Inc., Harcourt Brace
Jovanovich, Publisher) Editor-in-Chief David R.
I Dantzker, for the publication of the abstracts of posters
presented at this symposium (Vol. 1, no. 2, June
1986). Many of the section summaries reflect
information published in these abstracts and
presented as posters.
xii Acknowledgments
The financial supporters of this symposium and book are listed below in
alphabetical order:
Anaquest
Burroughs Wellcome Fund
The Council for Tobacco Research, Inc.-USA
Glaxo, Inc.
ICI Americas
Key Pharmaceuticals, Inc.
McNeil Pharmaceutical
Roerer Group, Inc.
Roerig
Smith, Kline and Beckman
The University of Wisconsin Graduate School
The University of Wisconsin Medical School
The Upjohn Company
Wyeth Laboratories, Inc.
EDITOR'S NOTE
The organizing committee and editors of this book
wish to express special thanks to the Journal of
Critical Care (Grune & Stratton, Inc., Harcourt Brace
Jovanovich, Publisher) Editor-in-Chief David R.
I Dantzker, for the publication of the abstracts of posters
presented at this symposium (Vol. 1, no. 2, June
1986). Many of the section summaries reflect
information published in these abstracts and
presented as posters.
An Overview of the Microscopic
Appearance of the Pulmonary Artery and
the Problems of Its Quantitation
WILLIAM M. THURLBECK1
Department of Pathology
University of British Columbia
Vancouver, B.C., Canada
I. INTRODUCTION
This chapter will briefly discuss the microscopic anatomy of the human
pulmonary arterial system. It will emphasise problems in quantitation and
expression of data that exist at present, and how various authors have attempted to
circumvent these. It is meant as an introduction to the paper by Dr. Wagenvoort,
who, with his vast experience in the pathology of the pulmonary vascular system,
will attempt to solve some of the problems that will be raised. I will also briefly
outline some findings in the pulmonary arterial system in the National Institutes
of Health (NIH) Nocturnal Oxygen Therapy Trial (NOTT), which illustrate well
some of the problems.
Interest in the anatomy and pathology of the human pulmonary arteries
became great in the 1950's when surgery for cardiac valvular disease lead to interest
in arterial changes in mitral stenosis. Cardiac surgery for congenital heart disease
further increased this interest, and special emphasis was placed on lesions that
might indicate reversibility or otherwise of pulmonary hypertension. The classical
grading system of Heath and Edwards was introduced (1). More contemporary
Supported by Grant # MT-7124, Medical Research Council of Canada,
and a grant from the British Columbia Heart Association.
The Pulmonary Circulation Copyright © 1987 by Academic Press, Inc.
in Health and Disease 3 All rights of reproduction in any form reserved.
4 William Μ. Thurlbeck
interest has been aroused by the suggestion that intra-operative lung frozen
sections may be important in guiding cardiac surgery (2). This topic will be
amplified by Dr. Langston later in this chapter.
II. PROBLEMS OF QUANTITATION AND DESCRIPTION
A. The problem of vasoconstriction,
and attempts at its solution
If vasoconstriction persists in the post-mortem interval, vessels may be
falsely classified into vessels of a smaller order. The classic example is in the
smallest arteries (less than 100 μηι) that are generally non-muscular. If
constriction of vessels of 100 |im and larger occurs, they will appear as the vessels
of the smaller set. Since arteries more than 100 μιη in diameter are usually
muscular, their false inclusion may lead to the conclusion that there is abnormal
development of muscle in the smallest arteries.
The reality, and the extent, of putative persistent vasoconstriction post­
mortem is not known with certainty. One approach has been to distend the
pulmonary arteries at high pressure so that all vessels dilate fully, and Reid's
laboratory has been the chief proponent of this technique (3). Rabinovitch et al.
(2), working in her laboratory, have indicated that medial thickness of the
pulmonary arteries may be two and a half times as large in undistended arteries
compared to distended arteries. Others have found a smaller change — an increase
in thickness of media to wall ratio of 7.8% (4) and a decrease in lumen diameter of
0.34 to 0.30 mm and an increase in medial thickness of 0.09 to 0.095 mm in non-
distended arteries compared to distended ones has been reported (5). These
differences are not statistically significant. Another approach is to correct
mathematically for the effect of vasoconstriction (6). This model assumes that the
internal elastic lamina is circular in cross section when fully distended. The length
of the crenated lamina is measured as seen in the undistended specimen and the
circumference and diameter as a circle then calculated. The area of the media is
measured and assumed to remain constant whether constricted or not. The
thickness of the media when the artery is fully distended can then be easily
calculated, from its area and the new diameter calculated from the internal elastica.
This technique was modestly time consuming and difficult, but is now done much
more quickly and easily with the use of computer-assisted digitizers. A third
approach uses a similar assumption that medial area remains constant. It has been
shown that the external adventitial diameter (from adventitial margin to adventitial
margin) of the bronchovascular sheath is independent of vascular distension (5),
Microscopic Appearance of the Pulmonary Artery 5
although of course dependent on intrabronchial inflation. Under these
circumstances, the ratio of medial or intimal area to total vessel area (marked at the
edge of the adventitia and/or halfway betwen the arterial wall and bronchial wall)
can be easily calculated (7). Whether the lumen area should be subtracted from
total vessel area to give total tissue area is not clear. Theoretically, a smaller area
is subtracted for total vascular area in the case of vasoconstriction, making the
denominator larger and the ratio smaller.
Finally, vessel dimensions and thickness (or area) can be measured at
marker structures, such as terminal bronchioles or respiratory bronchioles (8).
This is particularly useful in infants and children where corresponding orders of
vessel will normally be smaller than in adults.
The problems of morphometry of the pulmonary arterial system are
further discussed by Langston and Holder in this chapter.
B. Problems of counting
The number of arteries has been counted per unit area (2,9) and
abnormalities found in disease states. The problem is that one is interested in the
number per unit volume and the number per unit area is, in a sense, an optical
illusion. This is because the number of structures per unit area (N) is related to
A
the number per unit volume (N) as follows (10):
v
N-N**/B-V
V A VS
where Β is the shape constant describing the ratio between the volume of
the structure of interest and its average cross sectional area, and V is the volume
vs
proportion that structure, s, forms of the whole organ.
When re-written:
N rt3/2 = N -B.V
Aa Vart Vait
Hence the number seen in two dimensions is dependent not only on N
Vart
but also the shape constant and the volume proportion of the arteries. With
constriction, the shape constant may change dramatically as the length:diameter
ratio of the artery increases and will also change as the volume proportion of
arteries decreases.
6 William Μ. Thurlbeck
C. Problem of different artery sizes
It is by no means certain that arteries of different sizes have the same
thickness to diameter ratio, or muscle area to external elastic area or external
adventitial area. It may be that, say, vessels 100-150 μηι are different in medial or
intimal thickness from vessels 150-200 μηι in diameter. It may also be that
vessels of different sizes respond differently to disease conditions. With modern
computer processing, this problem may be easily and quickly solved, provided
vasoconstriction is not a major problem. For example, we have a programme in
which one touches the images of the lumen margin, internal elastica, external
elastica and external adventitia. Calculations are made of appropriate thickness
(intima, media, adventita) and placed in sets of 50 or 100 |im in diameter of either
external elastic diameter or external adventitial diameter and the data, including
statistics, processed automatically. The various areas can also be calculated by
tracing the perimeter of the boundaries and dealt with in a similar fashion.
D. The problem of normative data
It is generally taken for granted that control subjects should be without
heart or lung disease. An important variable is smoking. It has long been known
that smokers have increased intimal thickness (11), and more prominent bands of
longitudinal muscle cells in the intima (12). These observations have been
extended to show increased numbers of transected arteries less than 200 μηι in
diameter, increased medial muscle and intimal thickness in smokers (9). Others
have shown that the proportion of intimal area was increased in smokers, and was
more severe in patients with moderate compared to mild emphysema (7).
ΠΙ. THE NIH NOTT TRIAL
Lungs were available from 33 patients who entered this study. All had
chronic airflow obstruction with a resting P0 of less than 60 mmHg and had no
2
significant other disease. The average of death was 67 years. The first problem
was the controls. Some 1400 autopsy cases were on file that had a detailed
smoking history, autopsy report and paper-mounted whole lung sections. Only
seven patients within this group met the criteria of having no chronic heart or lung
disease (including chronic bronchitis) and had not smoked. Every measurement
possible was made including intimal and medial thickness and area, and related to
external elastica and external adventitial diameter and areas. The Yamaki correction
was applied (6) and the internal diameter of the vessels measured. Vessels were