Monocyte adherence to fibronectin: role of CD11/CD18 integrins and relationship to other monocyte functions

R Medicine > RC Internal medicine

Owen, Caroline Ann ; Stockley, Robert A.

University:University of Birmingham

Department:Medicine

关键词: R Medicine;    RC Internal medicine;   

Others  :  http://etheses.bham.ac.uk//id/eprint/36/1/Owen93PhD.pdf

来源: University of Birmingham eTheses Repository

【 摘 要 】

Regulated adherence of monocytes to extracellular matrix macromolecules is a prerequisite for their accumulation at sites of pulmonary infection and inflammation. To begin to assess the pathobiological importance of alterations in monocyte adherence to extracellular matrix in inflammatory lung diseases, the adherence properties of monocytes from patients with an inflammatory lung disease (bronchiectasis) and healthy subjects to a representative matrix component (fibronectin) were compared. Spontaneous adherence of monocytes from the control subjects was 20 to 25%, whereas that of the patients' cells was 2 to 3-fold higher and correlated with the severity of airway inflammation. Endotoxin (LPS) and cytokines from areas of airway disease are likely to be responsible for the observed monocyte activation since: 1) LPS was detected in plasma from all of the patients but none of the control subjects; and 2) LPS and cytokines produced dose-related increases in the adherence of normal monocytes in vitro. Monocyte adherence to fibronectin was substantially mediated by CD11/CD18 integrins, via both RGD-dependent and RGD-independent mechanisms. These data indicate that signals arising from foci of pulmonary inflammation are likely determinants of the accumulation of monocytes in the lungs of patients with chronic inflammatory lung diseases. There was a striking relationship between the adherence properties of monocytes and functions that are of biological importance at sites of inflammation. Spontaneously adherent monocytes had an "inflammatory effector" phenotype, non-adherent cells had an "immune modulatory" phenotype and monocytes that could stimulated to adhere by LPS (LPS-adherent cells) had an intermediate phenotype. In addition, only the adherent monocyte subpopulations were replete with HLE and these cells contained a substantial (10 to 11-fold) molar excess of HLE compared with the physiological inhibitor of this enzyme (a1-antitrypsin). Maturation in vitro increased the accumulation of a1-antitrypsin by all of the monocyte subpopulations. In contrast, proinflammatory mediators up-regulated a1-antitrypsin accumulation by only the spontaneously adherent cells, probably by translational or post-translational mechanisms. In conclusion, these data indicate that monocytes are heterogeneous in their ability to accumulate at sites of infection and inflammation. In addition, the capacity of monocytes to adhere to fibronectin is related to monocyte functions that are of biological importance at sites of infection and inflammation. Furthermore, LPS released from foci of infection, may induce the accumulation of monocytes with an inflammatory effector phenotype, and may thereby promote resolution of tissue infection. Alternatively, LPS may promote the recruitment of monocytes with capacity to contribute to HLE-mediated tissue injury.