Ozone-Induced Acute Pulmonary Injury in Inbred Mouse Strains

Abstract

To determine if host factors influence the time course and extent of lung injury after acute inhalation of ozone (O3), we evaluated the physiologic and biologic response of nine genetically diverse inbred strains of mice (C57BL/6J, 129/SvIm, BTBR, BALB/cJ, DBA/2J, A/J, FVB/NJ, CAST/Ei, and C3H/HeJ) exposed to O3 (2.0 ppm x 3 h). Whole lung lavage determined that 129/Svlm, BTBR, DBA/2J, and FVB/NJ had a peak increase in polymorphonuclear cells (PMNs) at 6 h, whereas C57BL/6J and CAST/Ei had a peak increase at 24 h after exposure; airway PMNs were minimally elevated in A/J and C3H/HeJ; BALB/cJ had a predominant lymphocytic influx. Interleukin-6 concentration in the lavage fluid was associated with the influx of PMNs, whereas the total protein in the lavage fluid did not always correlate with lavage cellularity. Respiratory responses were monitored using whole body plethysmography and enhanced pause index. C57BL/6J, BALB/cJ, 129/SvIm, and BTBR were highly sensitive to O3 and exhibited significant increases in enhanced pause to methacholine aerosol stimulation at 6 and 24 h after exposure to O3. In contrast, DBA/2J, A/J, FVB/NJ, CAST/Ei, and C3H/HeJ strains had demonstrated increases in sensitivity to MCh at 6 h after exposure, but responses had returned to near baseline by 24 h after exposure to O3. Epithelial cell proliferation as assessed by proliferating cell nuclear antigen staining was evident at 24 h after exposure to O3. C57BL/6J and A/J showed 4% proliferating cell nuclear antigen-positive cells; 129/SvIm, DBA/2J, and FVB/NJ had 1-3%; and BTBR, BALB/cJ, CAST/Ei, and C3H/HeJ had < 1%. Phenotypic measurements in six inbred strains were used for an in silico genome analysis based on the Roche mouse database. Consistent loci on chromosomes 1, 7, and 15 were among those identified to have a significant association with the phenotypes studied. In aggregate, our approach has identified O3-resistant (C3H/HeJ and A/J) and -vulnerable (C57BL/6J and 129/SvIm) strains of mice, and determined novel genomic loci, suggesting a clear genetic basis for the lung response to inhaled O3.

RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

“…(34). These models have been optimized and validated in multiple publications (34). We observed significant O 3 -induced AHR, with airway resistance increasing from ∼0.7 up to 1.8-2.6 cm H 2 O/mL/s ( Fig.…”

“…We tested whether GRP blockade alters AHR and airways inflammation by using BALB/c females, which respond to both O 3 and OVA (34,35). Females are preferred because they have higher levels of X-linked GRPR (36).…”

“…S1), representing 157-271% increased airway resistance over filtered air (FA) controls at baseline. This model has been used successfully in multiple laboratories (34,37,38). A recent report (39) showed the kinetics (6-48 h after exposure) of inflammation and robust AHR development to methacholine (MCh) 24 h after O 3 .…”

Bone microstructure and its associated genetic variability in 12 inbred mouse strains: μCT study and in silico genome scan

“…A computational genome mapping approach has been recently used by our group in identification of chromosome regions associated with different type of phenotypic responses [43,44]. This program uses a murine genome single nucleotide polymorphism (SNP) database developed by Roche Bioscience (Palo Alto, CA) to identify chromosomal regions associated with different phenotypes complex traits.…”

“…In addition, in silico genome scan allowed us to identify chromosomal regions containing genetic factors regulating inter-strain skeletal phenotype variability [43,44]. The advent of in silico genetic mapping may allow investigators to gain rapid insight into the genetic underpinnings of inter-strain trait differences [43].…”