Highlights
Candidate genes controlling pulmonary function in mice.
- Evolution of COPD compared to other chronic diseases
Impaired development and reduced lung capacity are risk factors of asthma and chronic obstructive pulmonary disease. Previously, our genomewide linkage analysis of C3H/HeJ (C3H) and JF1/Msf (JF1) mouse strains identified quantitative trait loci (QTLs) associated with the complex traits of dead space volume (VD), total lung capacity (TLC), lung compliance (CL), and diffusing capacity for CO (DCO). We assessed positional candidate genes by comparing C3H with JF1 lung transcript levels by microarray and by comparing C3H, BALB/cByJ, C57BL/6J, A/J, PWD/PhJ, and JF1 strains, using exon sequencing to predict protein structure. Microarray identified >900 transcripts differing in C3H and JF1 lungs related to lung development, function, and remodeling. Of these, three genes localized to QTLs associated with differences in lung function. C3H and JF1 strains differed in transcript and protein levels of superoxide dismutase 3, extracellular [SOD3; mouse chromosome (mCh) 5: VD] and transcript of trefoil factor 2 (TFF2; mCh 17: TLC and DCO), and ectonucleotide pyrophosphatase/p hosphodiesterase 2 (ENPP2; mCh 15: TLC and CL). Nucleotide sequencing of
Sod3, Tff2, and previously identified Relaxin 1 (Rln1; mCh 19: CL) uncovered polymorphisms that could lead to nonsynonymous amino acid changes and altered predicted protein structure. Gene-targeted Sod3+/+ mice had increased conducting airway volume (VD/TLC) compared with strain-matched control Sod3+/+ mice, consistent with the QTL on mCh 5. Two novel genes (Tff2 and Enpp2) have been identified and two suspected genes (Sod3 and Rln1) have been supported as determinants of lung function in mice. Findings with gene-targeted mice suggest that SOD3 is a contributing factor defining the complex trait of conducting airway volume.
Ganguly, K., Stoeger, T., Wesselkamper, S. C., Reinhard, C., Sartor, M. A., Medvedovic, M., Tomlinson, C. R., Bolle, I., Mason, J. M., Leikauf, G. D. and Schulz, H.: Candidate genes controlling pulmonary function in mice: transcript profiling and predicted protein structure. Physiol Genomics 31, 410-21 (2007).
Efficient elimination of inhaled nanoparticles from the alveolar region and supsequent re-entrainment onto airways epithelia.
Present textbooks state that all inhaled particles which deposited on the epithelial lung surface, stay there until alveolar macrophages (AM) as the front line of the defence system phagocytose them for further disintegration and removal. We observed that
(1) only a small fraction of deposited nanoparticles (NP, particles < 100nm) are phagocytosed by AM and most NP disappear from the epithelial surface within 1-2 days but stay in lung tissue, i.e. epithelium, interstitial spaces and vascular endothelium. (Long-term in vivo studies by sequential lung retention, clearance, organ / tissue and broncho-alveolar-lavage (BAL) measurements in healthy adult WKY rats at various time points over 6 month after a single one-hour-inhalation of 192Ir radiolabeled iridium NP). E.g. from three weeks to six months after inhalation more than 80% of the retained Ir NP in the lungs were translocated into lung tissue. In comparison 80% of micron-sized particles retained in the lungs were found in AM on the epithelium. Hence, there is a strong size-dependent difference in particle translocation across the air-blood-barrier: most NP have immediate access to lung tissue while micron-sized particles don’t.
(2) Furthermore, AM-mediated NP clearance to the larynx originates not only from the NP fraction retained on the epithelium but mostly from NP after re-entrainment from the interstitium to the luminal side of epithelium. Surprisingly, NP recruited mainly from lung tissues across the epithelium are cleared towards the larynx for fecal excretion with the same kinetics (i.e. same daily fractions) as micron-sized particles being retained all time on the epithelial surface.
We conclude that NP are much less phagocytosed by AM than micron-sized particles but are effectively removed from the lung surface towards its tissues. Even from these interstitial sites they re-appear on the epithelial surface and undergo AM-mediated long-term NP clearance to the larynx. Based on these results we assume that there are different biological-NP interactions (NP coating with surfactant, NP-protein complexing, receptor binding, endocytosis of epithelial cells) that leads to translocation of NP into lung tissue as well as into circulation and towards secondary target organs. Identification of the underlying mechanisms leading to these NP translocation pathways will be an important step in the risk assessment of inhaled NP.
Semmler-Behnke M, Takenaka S, Fertsch S, Wenk A, Seitz J, Mayer P, Oberdörster G and Kreyling W G. 2007. Efficient Elimination of Inhaled Nanoparticles from the Alveolar Region: Evidence for Interstitial Uptake and Subsequent Reentrainment onto Airways Epithelium. Environmental Health Perspectives Vol. 115, 5:728-733
Aerosol Network
Brochure on the Campus Aerosol Network (German) pdf
