Inbred strain variation in lung function
Institute for Inhalation Biology, GSF-National Research Center for Environment and Health, D-85758 Neuherberg/Munich, Germany
Institute of Experimental Genetics, GSF-National Research Center for Environment and Health, D-85758 Neuherberg/Munich, Germany
Received: 7 January 2002 / Accepted: 19 April 2002
Abstract. The purpose of the present study was to determine
the strain-speci®c phenotype variance of lung function pa-
rameters among common inbred laboratory mouse strains. In
accordance with the ``Mouse Phenome Project'' run by The
Jackson Laboratory (http://www.jax.org/phenome), lung vol-
umes, lung mechanics, and diusing capacity of 16 males and
16 females of the strains C3H/HeJ, BALB/cByJ, C57B1/6J, A/
J, FVB/J, 129SV/ImJ, and SWR/J were determined in a
standardized manner. The de®ned respiratory maneuvers for
lung function testing were performed with a custom-made,
computer-controlled servo-ventilator in anesthetized animals.
Sex dierences within the strains were found in most (83%)of
the absolute lung function parameters. Usually, normalization
to body or lung size completely compensates for the observed
gender dierences. There was great diversity between strains
for all of the lung function parameters studied; for example,
the total lung capacity as well as the pulmonary diusing ca-
pacity for carbon monoxide varied by 50% and the static lung
compliance by a factor of almost two among the strains. Little,
but statistically signi®cant variability was detectable for the
dead space volume and the respiratory system resistance.
There was no clear-cut evidence for any strain exhibiting either
the smallest or the largest values for all parameters studied,
suggesting that there were no simple allometric relationships of
lung size between the strains. Well-established genealogical
relationships among strains were not constantly re¯ected in
phenotype similarities of pulmonary function. Therefore, these
data strongly support heritable genetic traits for pulmonary
function. Moreover, it constitutes a basis for further genetic
lung function-related studies.
During the last decade, major eorts were put in the se-
quencing of the human genome. Recently, the whole sequence
of the human genome has been published, and a public se-
quence of the mouse will also soon be available. Despite the
availability of complete genetic sequences, the knowledge
characterizing gene functions is still very limited. To get access
to human gene functions, the mouse serves as a central model
organism. Comparing phenotype and genotype of mutants or
knockouts helps to identify the function of genes within the
very complex organism. However, there is an increasing need
for comprehensive phenotype characterization for the variety
of existing mutants but, even more pressing, for commonly
used laboratory inbred mouse strains. In line with the purpose
of the ``Mouse Phenome Project'' run by The Jackson Labo-
ratory (Paigen and Eppig 2000), our work aimed to constitute
new techniques and baseline data for pulmonary functions of
commonly used and genetically diverse inbred mouse strains.
A basic set of lung function parameters is presented charac-
terizing lung volumes, lung elasticity, airway resistance, in-
trapulmonary gas mixing, and alveolar-capillary gas transfer.
These data will be available for public access through the
``Mouse Phenome Database'' (http://www.jax.org/phenome).
The purpose of the present study was (i) to determine the
strain-speci®c phenotype variance of pulmonary function
among common inbred laboratory mouse strains and (ii) to
assess whether well-established genealogical relationships
among strains (Atchley and Fitch 1991) are re¯ected in phe-
notype similarities of pulmonary function. Finally, the data are
also supposed to serve as references for physiological com-
parisons between untreated healthy mice and pathological
phenotypes, such as developmental failure in alveogenesis
(Hogan 1999; Weinstein et al. 1998), to identify signi®cant
physiological abnormalities in pulmonary function.
Materials and methods
In accordance with the ``Mouse Phenome Project'' run by
The Jackson Laboratory, classifying the strains in priority groups A,
B, and C, the strains C3H/HeJ (C3), BALB/cByJ (BALB), C57B1/6J
(B6), A/J (A), FVB/J (FVB), 129SV/ImJ (129) of priority group A and
the strain SWR/J (SWR) of priority group B were chosen. The strains
have all been established at The Jackson Laboratory in Bar Harbor,
Me. At the age of 10±11 weeks, the animals were shipped to the GSF.
All strains were kept at the GSF in ``isolated ventilated cages'' (IVC-
Racks, BioZone) in a 12 h/12 h light/dark cycle with lights coming on
at 06.00 a.m. Food and water were available ad libitum. Sixteen males
and 16 females from each strain, aged between 12 and 14 weeks, were
used in all lung function tests. The use of the animals was in accor-
dance with the German Law on Animal Protection and approved by
the Bavarian Animal Research Authority.
Lung function tests were performed between 9.00 a.m.
and 5.00 p.m. To account for a possible eect of the circadian rhythm,
the sequence of measurements was ``randomized''. Two males were
tested in the morning, and two females in the afternoon. The sequence
was changed on the next day.
To avoid as much stress as possible prior to the
investigation, anesthesia was induced by inhalation of iso¯urane (5%)
for 1 min in a whole-body box and continued with an intraperitoneal
injection of a mixture of xylazine and ketamine (4.1 mg/kg body weight
and 188.3 mg/kg body weight, respectively). The animals were then
intubated according to the method described by Brown and coworkers
(1999). A commonly used 28 G i.v.-catheter (31-mm-long catheter, OD
1.1 mm; Sims Portex) was used as an endotracheal tube and inserted 10
mm deep into the trachea. The animals were attached to the ventilator
and ventilated at rates of 120±130 breaths/min with a tidal volume of
280±325 ll. The individual ventilation parameters were set so that the
endotracheal peak inspiratory pressure was about 10 cmH
physiological end-expiratory CO
reached. For maintaining anesthesia during lung function tests, an air
Mammalian Genome 13, 429±437 (2002).
Correspondence to: C. Reinhard; E-mail: email@example.com or H.
Schulz; E-mail: firstname.lastname@example.org