Abstract
The deformations of neutrophils as they pass through the pulmonary microcirculation affect their transit time, their tendency to contact and interact with the endothelial surface, and potentially their degree of activation. Here we model the cell as a viscoelastic Maxwell material bounded by constant surface tension and simulate indentation experiments to quantify the effects of (N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-stimulation on its mechanical properties (elastic shear modulus and viscosity). We then simulate neutrophil transit through individual pulmonary capillary segments to determine the relative effects of capillary geometry and fMLP-stimulation on transit time. Indentation results indicate that neutrophil viscosity and shear modulus increase by factors of 3.4, for 10(-9) M fMLP, and 7.3, for 10(-6) M fMLP, over nonstimulated cell values, determined to be 30.8 Pa.s and 185 Pa, respectively. Capillary flow results indicate that capillary entrance radius of curvature has a significant effect on cell transit time, in addition to minimum capillary radius and neutrophil stimulation level. The relative effects of capillary geometry and fMLP on neutrophil transit time are presented as a simple dimensionless expression and their physiological significance is discussed.
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- Damiano E. R. The effect of the endothelial-cell glycocalyx on the motion of red blood cells through capillaries. Microvasc Res. 1998 Jan;55(1):77–91. doi: 10.1006/mvre.1997.2052. [DOI] [PubMed] [Google Scholar]
- Doerschuk C. M., Beyers N., Coxson H. O., Wiggs B., Hogg J. C. Comparison of neutrophil and capillary diameters and their relation to neutrophil sequestration in the lung. J Appl Physiol (1985) 1993 Jun;74(6):3040–3045. doi: 10.1152/jappl.1993.74.6.3040. [DOI] [PubMed] [Google Scholar]
- Doerschuk C. M. Mechanisms of leukocyte sequestration in inflamed lungs. Microcirculation. 2001 Apr;8(2):71–88. [PubMed] [Google Scholar]
- Dong C., Skalak R. Leukocyte deformability: finite element modeling of large viscoelastic deformation. J Theor Biol. 1992 Sep 21;158(2):173–193. doi: 10.1016/s0022-5193(05)80716-7. [DOI] [PubMed] [Google Scholar]
- Dong C., Skalak R., Sung K. L. Cytoplasmic rheology of passive neutrophils. Biorheology. 1991;28(6):557–567. doi: 10.3233/bir-1991-28607. [DOI] [PubMed] [Google Scholar]
- Dong C., Skalak R., Sung K. L., Schmid-Schönbein G. W., Chien S. Passive deformation analysis of human leukocytes. J Biomech Eng. 1988 Feb;110(1):27–36. doi: 10.1115/1.3108402. [DOI] [PubMed] [Google Scholar]
- Drury J. L., Dembo M. Hydrodynamics of micropipette aspiration. Biophys J. 1999 Jan;76(1 Pt 1):110–128. doi: 10.1016/S0006-3495(99)77183-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Evans E., Kukan B. Passive material behavior of granulocytes based on large deformation and recovery after deformation tests. Blood. 1984 Nov;64(5):1028–1035. [PubMed] [Google Scholar]
- Evans E., Yeung A. Apparent viscosity and cortical tension of blood granulocytes determined by micropipet aspiration. Biophys J. 1989 Jul;56(1):151–160. doi: 10.1016/S0006-3495(89)82660-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fenton B. M., Wilson D. W., Cokelet G. R. Analysis of the effects of measured white blood cell entrance times on hemodynamics in a computer model of a microvascular bed. Pflugers Arch. 1985 Apr;403(4):396–401. doi: 10.1007/BF00589252. [DOI] [PubMed] [Google Scholar]
- Frank R. S., Tsai M. A. The behavior of human neutrophils during flow through capillary pores. J Biomech Eng. 1990 Aug;112(3):277–282. doi: 10.1115/1.2891185. [DOI] [PubMed] [Google Scholar]
- Guntheroth W. G., Luchtel D. L., Kawabori I. Pulmonary microcirculation: tubules rather than sheet and post. J Appl Physiol Respir Environ Exerc Physiol. 1982 Aug;53(2):510–515. doi: 10.1152/jappl.1982.53.2.510. [DOI] [PubMed] [Google Scholar]
- Hochmuth R. M., Ting-Beall H. P., Beaty B. B., Needham D., Tran-Son-Tay R. Viscosity of passive human neutrophils undergoing small deformations. Biophys J. 1993 May;64(5):1596–1601. doi: 10.1016/S0006-3495(93)81530-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hogg J. C., Coxson H. O., Brumwell M. L., Beyers N., Doerschuk C. M., MacNee W., Wiggs B. R. Erythrocyte and polymorphonuclear cell transit time and concentration in human pulmonary capillaries. J Appl Physiol (1985) 1994 Oct;77(4):1795–1800. doi: 10.1152/jappl.1994.77.4.1795. [DOI] [PubMed] [Google Scholar]
- Huang Y., Doerschuk C. M., Kamm R. D. Computational modeling of RBC and neutrophil transit through the pulmonary capillaries. J Appl Physiol (1985) 2001 Feb;90(2):545–564. doi: 10.1152/jappl.2001.90.2.545. [DOI] [PubMed] [Google Scholar]
- Lien D. C., Henson P. M., Capen R. L., Henson J. E., Hanson W. L., Wagner W. W., Jr, Worthen G. S. Neutrophil kinetics in the pulmonary microcirculation during acute inflammation. Lab Invest. 1991 Aug;65(2):145–159. [PubMed] [Google Scholar]
- Lien D. C., Wagner W. W., Jr, Capen R. L., Haslett C., Hanson W. L., Hofmeister S. E., Henson P. M., Worthen G. S. Physiological neutrophil sequestration in the lung: visual evidence for localization in capillaries. J Appl Physiol (1985) 1987 Mar;62(3):1236–1243. doi: 10.1152/jappl.1987.62.3.1236. [DOI] [PubMed] [Google Scholar]
- Lien D. C., Worthen G. S., Capen R. L., Hanson W. L., Checkley L. L., Janke S. J., Henson P. M., Wagner W. W., Jr Neutrophil kinetics in the pulmonary microcirculation. Effects of pressure and flow in the dependent lung. Am Rev Respir Dis. 1990 Apr;141(4 Pt 1):953–959. doi: 10.1164/ajrccm/141.4_Pt_1.953. [DOI] [PubMed] [Google Scholar]
- Lipowsky H. H., Riedel D., Shi G. S. In vivo mechanical properties of leukocytes during adhesion to venular endothelium. Biorheology. 1991;28(1-2):53–64. doi: 10.3233/bir-1991-281-206. [DOI] [PubMed] [Google Scholar]
- Motosugi H., Graham L., Noblitt T. W., Doyle N. A., Quinlan W. M., Li Y., Doerschuk C. M. Changes in neutrophil actin and shape during sequestration induced by complement fragments in rabbits. Am J Pathol. 1996 Sep;149(3):963–973. [PMC free article] [PubMed] [Google Scholar]
- Needham D., Hochmuth R. M. Rapid flow of passive neutrophils into a 4 microns pipet and measurement of cytoplasmic viscosity. J Biomech Eng. 1990 Aug;112(3):269–276. doi: 10.1115/1.2891184. [DOI] [PubMed] [Google Scholar]
- Pries A. R., Secomb T. W., Gaehtgens P. The endothelial surface layer. Pflugers Arch. 2000 Sep;440(5):653–666. doi: 10.1007/s004240000307. [DOI] [PubMed] [Google Scholar]
- Pries A. R., Secomb T. W., Jacobs H., Sperandio M., Osterloh K., Gaehtgens P. Microvascular blood flow resistance: role of endothelial surface layer. Am J Physiol. 1997 Nov;273(5 Pt 2):H2272–H2279. doi: 10.1152/ajpheart.1997.273.5.H2272. [DOI] [PubMed] [Google Scholar]
- Rostgaard J., Qvortrup K. Electron microscopic demonstrations of filamentous molecular sieve plugs in capillary fenestrae. Microvasc Res. 1997 Jan;53(1):1–13. doi: 10.1006/mvre.1996.1987. [DOI] [PubMed] [Google Scholar]
- Saito Hajime, Lai Jean, Rogers Rick, Doerschuk Claire M. Mechanical properties of rat bone marrow and circulating neutrophils and their responses to inflammatory mediators. Blood. 2002 Mar 15;99(6):2207–2213. doi: 10.1182/blood.v99.6.2207. [DOI] [PubMed] [Google Scholar]
- Schmid-Schönbein G. W., Sung K. L., Tözeren H., Skalak R., Chien S. Passive mechanical properties of human leukocytes. Biophys J. 1981 Oct;36(1):243–256. doi: 10.1016/S0006-3495(81)84726-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Skalak R., Dong C., Zhu C. Passive deformations and active motions of leukocytes. J Biomech Eng. 1990 Aug;112(3):295–302. doi: 10.1115/1.2891187. [DOI] [PubMed] [Google Scholar]
- Sung K. L., Dong C., Schmid-Schönbein G. W., Chien S., Skalak R. Leukocyte relaxation properties. Biophys J. 1988 Aug;54(2):331–336. doi: 10.1016/S0006-3495(88)82963-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ting-Beall H. P., Lee A. S., Hochmuth R. M. Effect of cytochalasin D on the mechanical properties and morphology of passive human neutrophils. Ann Biomed Eng. 1995 Sep-Oct;23(5):666–671. doi: 10.1007/BF02584463. [DOI] [PubMed] [Google Scholar]
- Tran-Son-Tay R., Kan H. C., Udaykumar H. S., Damay E., Shyy W. Rheological modelling of leukocytes. Med Biol Eng Comput. 1998 Mar;36(2):246–250. doi: 10.1007/BF02510753. [DOI] [PubMed] [Google Scholar]
- Tran-Son-Tay R., Kirk T. F., 3rd, Zhelev D. V., Hochmuth R. M. Numerical simulation of the flow of highly viscous drops down a tapered tube. J Biomech Eng. 1994 May;116(2):172–177. doi: 10.1115/1.2895716. [DOI] [PubMed] [Google Scholar]
- Tran-Son-Tay R., Needham D., Yeung A., Hochmuth R. M. Time-dependent recovery of passive neutrophils after large deformation. Biophys J. 1991 Oct;60(4):856–866. doi: 10.1016/S0006-3495(91)82119-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsai M. A., Frank R. S., Waugh R. E. Passive mechanical behavior of human neutrophils: power-law fluid. Biophys J. 1993 Nov;65(5):2078–2088. doi: 10.1016/S0006-3495(93)81238-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vink H., Duling B. R. Identification of distinct luminal domains for macromolecules, erythrocytes, and leukocytes within mammalian capillaries. Circ Res. 1996 Sep;79(3):581–589. doi: 10.1161/01.res.79.3.581. [DOI] [PubMed] [Google Scholar]
- Warnke K. C., Skalak T. C. In vivo measurement of leukocyte viscosity during capillary plugging. J Biomech Eng. 1992 Nov;114(4):533–538. doi: 10.1115/1.2894107. [DOI] [PubMed] [Google Scholar]
- Wiggs B. R., English D., Quinlan W. M., Doyle N. A., Hogg J. C., Doerschuk C. M. Contributions of capillary pathway size and neutrophil deformability to neutrophil transit through rabbit lungs. J Appl Physiol (1985) 1994 Jul;77(1):463–470. doi: 10.1152/jappl.1994.77.1.463. [DOI] [PubMed] [Google Scholar]
- Worthen G. S., Schwab B., 3rd, Elson E. L., Downey G. P. Mechanics of stimulated neutrophils: cell stiffening induces retention in capillaries. Science. 1989 Jul 14;245(4914):183–186. doi: 10.1126/science.2749255. [DOI] [PubMed] [Google Scholar]
- Yeung A., Evans E. Cortical shell-liquid core model for passive flow of liquid-like spherical cells into micropipets. Biophys J. 1989 Jul;56(1):139–149. doi: 10.1016/S0006-3495(89)82659-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zahalak G. I., McConnaughey W. B., Elson E. L. Determination of cellular mechanical properties by cell poking, with an application to leukocytes. J Biomech Eng. 1990 Aug;112(3):283–294. doi: 10.1115/1.2891186. [DOI] [PubMed] [Google Scholar]
- Zhelev D. V., Needham D., Hochmuth R. M. Role of the membrane cortex in neutrophil deformation in small pipets. Biophys J. 1994 Aug;67(2):696–705. doi: 10.1016/S0006-3495(94)80529-6. [DOI] [PMC free article] [PubMed] [Google Scholar]