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Effect of tobacco smoke on leucocyte adhesion in vivo

Institution: La Jolla Institute for Molecular Medicine
Investigator(s): Pragada Sriramarao, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0171 Award: $1,023,946
Subject Area: Pulmonary Disease
Award Type: Research Project Awards

Initial Award Abstract
One of the important etiological factors in smoking induced airway inflammation (including COPD) is the recruitment of white blood cells (leukocytes) into the airways. This relationship appears to strengthen with the number of cigarettes smoked and the amount of smoke inhaled. At a cellular level, airway inflammation is characterized by the recruitment of circulating leukocytes into extravascular spaces of the lung. However, the molecular mechanisms mediating leukocyte-blood vessel interactions in the lungs of smokers suffering from airway inflammation are not well understood.

Our preliminary studies suggest that exposure of mice to Environmental Tobacco Smoke (ETS) results in the formation of new blood vessels i.e., angiogenesis - within the lung tissue. This exposure also results in the activation of blood vessels leading to increased leukocyte interactions in lung microvessels. Thus increased angiogenesis and the simultaneous recruitment of circulating leukocytes in the airways could exacerbate episodes of airway inflammation (such as chronic bronchitis) in smokers. Therefore a reduction of airway inflammation via inhibition of ETS induced lung angiogenesis or inhibition of recruitment of activated inflammatory leukocytes into the airways of first hand and second smokers, could result in alleviation of smoking mediated tissue damage.

Our previously funded TRDRP studies (7RT-0197) demonstrated that in vivo exposure of mice to cigarette smoke and in vitro exposure of bone marrow cells to nicotine results in the inhibition of hematopoiesis (i.e., reduced formation of new blood cells). Additional studies have demonstrated that exposure to cigarette smoke results in the increased number of circulating mature blood cells and their progenitors in the peripheral blood of mice. Coupled with recent clinical observations demonstrating the presence of progenitor cells in the peripheral blood of patients suffering from airway inflammation, we hypothesize that exposure to ETS alters bone marrow hematopoiesis or generation of blood cells in smokers. Since all inflammatory leukocytes are generated in the bone marrow, understanding how the bone marrow responds to chronic ETS exposure may be central to understanding airway inflammation. We will compare the number of progenitor cells isolated from the peripheral blood of smokers and normal individuals and evaluate how these cells interact with inflamed blood vessels under conditions of blood flow in animal models of inflammation.

The proposed grant application will apply the current knowledge of immunology, vascular and cell biology in understanding the cellular mechanisms that mediate leukocyte adhesion to inflamed blood vessels of the systemic vs. lung microcirculation. Furthermore, using the technique of intravital microscopy, it will be possible to visualize the interaction of circulating cells within ETS exposed lung microvessels in vivo. Results obtained from these studies will identify what specific receptors and adhesion molecules contribute to leukocyte sequestration during episodes of airway inflammation that afflicts both first and second hand smokers. The knowledge derived from these studies will help in developing therapeutic strategies to ameliorate smoking related pulmonary disease in humans.

A murine model to study leukocyte rolling and intravascular trafficking in lung microvessels.
Periodical: American Journal of Pathology Index Medicus:
Authors: Sikora L, Johansson A, Hughes G, Rao SP, Broide DH, Sriramarao, P ART
Yr: 2003 Vol: 169 Nbr: Abs: Pg: 2019-2028

Constitutive over-expression of IL-5 induces extramedullary hematopoiesis in the spleen.
Periodical: Blood Index Medicus:
Authors: Khaldoyanidi S, Sikora L, Rotherberg M, Broide DH, Sriramarao P ART
Yr: 2003 Vol: 101 Nbr: Abs: Pg: 863-868

Selectin-dependent rolling and adhesion of leukocytes in nicotine-exposed lung microvessels.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Sikora L, Rao SP, Sriramarao P ART
Yr: 2003 Vol: 285 Nbr: Abs: Pg: L654-663

Serotonin is a chemotactic factor for eosinophils and functions additively with eotaxin.
Periodical: Journal of Immunology Index Medicus:
Authors: Sriramarao P, Boehme SA, Lio FM, Sikora L, Pandit T, Lavrador K, Rao SP ART
Yr: 2004 Vol: 173 Nbr: Abs: Pg: 3599-3603