Comparison of pulmonary response among two mouse strains with divergent lung function following carbon nanoparticle instillation.

Rationale: Individuals with lower basal lung function are at higher risk for particulate matter associated respiratory diseases. Carbon nanoparticles (CNP) possess an emerging source of exposure due to the massive release of combustion products and nanotechnological revolution. Pulmonary inflammation caused by the deposited CNP attributes for their adverse health effects. To address these physio-toxicological issues in an experimental setup, we selected C3H/HeJ (C3) and JF1/Msf (JF1) mouse strains with divergent lung function and studied the elicited inflammation and its resolution following CNP exposure. Results: Polymorphonuclear leucocyte (PMN) influx caused by 20µg CNP in JF1 exceeded that of C3 mice by 3-fold on day1. Kinetics of PMN clearance was also less efficient in JF1 as indicated by PMN count reaching baseline levels on day 7 in C3 but remained 15-fold high in JF1. On day 7 a strong influx of macrophages and lymphocytes was noted in JF1 bronchoalveolar lavage (BAL) suggesting chronification. After complete resolution of PMN influx on day 7 in C3 mice, we detected elevated concentrations of 20 markers that included IL1B, IL18, FGF2, EDN1, and VEGF in lung tissue and BAL. Biological pathway analysis revealed these factors to be involved in a closely regulated molecular cascade with IL1B/IL18 as upstream and FGF2/EDN1/VEGF as downstream molecules. This pathway was not triggered in JF1.  Conclusion:  Considering the role of the identified pathway in defence, development and morphogenesis we suggest a homeostatic machinery to be activated to counter the CNP challenge in C3 but not in JF1. Therefore JF1 mice with impaired lung function are more susceptible to CNP.   Supported by NGFN grants 01GS0120, 1GR0430, and 01GS0850