Abstract
Maedi is a chronic lymphoid interstitial pneumonia (LIP) of sheep caused by the lentivirus,
maedi-visna virus (MW). Following a long prepatent phase maedi progresses to clinical disease
characterised by exercise intolerance and dyspnoea. Although maedi is well characterised at a
pathological level, physiological studies of the disease have not been undertaken. As a consequence,
the nature of the functional abnormality that underlies the clinical disease is unknown, whether there
exists measurable functional deficit in the preclinical phase of the disease is unknown and the
relationship between lung pathology and functional deficit is unknown. These questions are
fundamental to understanding the way in which pathological events ultimately conspire to bring
about organ dysfunction and clinical disease. Further, knowledge of the way in which pathology
relates to measurable lung dysfunction offers a potential means of assessing the progress and
prognosis of this disease. This thesis describes an investigation into the pathophysiological
mechanisms responsible for inducing lung functional deficits in maedi.
As a prelude to establishing the nature of the functional deficit in maedi, repeated
measurements of static lung compliance (Cst), lung distensibility (K), effective alveolar volume
(VA,eff) and transfer factor for carbon monoxide (TL,CO,'sb') were made in anaesthetized control
sheep, seronegative for MW, over a period of 5 months. This study furnished regression equations
and prediction intervals for lung function indices in normal sheep using bodyweight as the
independent variable. By comparison with predicted normal values sheep naturally infected with
MW had reduced lung volumes and gas diffusing capabilities and increased lung elastic recoil.
A pathophysiological study was instigated to identify structural correlates of lung
functional deficits. Preliminary investigation involved the quantitative morphometric
characterisation of the normal sheep lung. Data from this study indicated that the ratio of fixed to
physiological lung volume ranged from 0.49 to 0.59 and that this ratio was positively correlated
with the time between euthanasia and inflation fixation of the lungs. Values for tissue volume
fraction within the lung parenchyma (Fvt) ranged from 0.18 to 0.25 and values for alveolar surface
density (Svt) ranged from 592 to 716 cm2/cm3. Pathophysiological correlations in MW-infected
sheep indicated that lung volume and transfer factor measurements were more sensitive indices of
pathology than measurements of Cst or K. Transfer factor was reduced even in sheep with minimal
histopathology suggesting this index as a sensitive means of assessing this condition. The density of
surface forces could not account for variation in K seen in vivo, however tissue factors such as the
quantity and functional tone of contractile tissue in the parenchyma, airways or blood vessels may
contribute. Given that parenchymal smooth muscle hyperplasia is a pathological feature of maedi, it
was hypothesized that this tissue element is responsible for the observed reduction in K.
In order to further investigate this relationship, the distribution and morphometric
quantitation of a-smooth muscle actin (ASMA) in lung parenchyma from normal and MW-infected
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sheep was determined and related to in vivo functional measurements. The volume density of
ASMA (IVASMA1) was negatively correlated with K and Cst, however partial correlation
coefficients indicated that IVASMA' and Fvt were strongly interdependent thus complicating
interpretation of the link between Fv'ASMA' and K. In order to separate the influence of dynamic
and passive tissue elements, histamine and clenbuterol were administered to normal and MWinfected
sheep in an attempt to cause relaxation and contraction of parenchymal contractile tissue.
The functional response of the cardiopulmonary system to intravenous infusion of these agents was
measured and correlated with Fv'ASMA'. K and Cst were significantly increased following
clenbuterol injection, however only the increase in K was correlated with the quantity of Fv'ASMA',
and this correlation was negative. These results could be explained if the site of action of
clenbuterol was not the contractile tissue at the level of the alveolar ducts, but rather that which
surrounds conducting airways.The dose of histamine required to lower dynamic compliance to 65%
of baseline values was negatively correlated with Fv'ASMA' and the attendant percentage change in
K was positively correlated with Fv'ASMA'. These findings support the contention that parenchymal
contractile tissue is of functional relevance and capable of regulating overall lung elastic properties.
Maedi is a naturally occurring disease in sheep in which the aetiologic agent and target cell
is known and in which the pathology is well characterised. As such it has potential as a model for
LIP associated with human immunodeficiency virus infection in children and adults. The present
study has both served to establish the functional characteristics of this disease and indicate structural
correlates of observed functional deficits. Moreover, evidence is presented to suggest that the
observed reduction in lung distensibility in maedi is a consequence of increased tissue forces
associated with the parenchymal smooth muscle hyperplasia that is a feature of this disease.
