The emigration of leukocytes from the pulmonary capillaries into the parenchyma is a critical step in the inflammatory response within the lung. Neutrophil emigration in response to stimuli within the lung occurs through two pathways, one that requires the leukocyte adhesion molecule, CD11/CD18 and one that does not. Which pathway is utilized depends on the stimulus. Stimuli that elicit CD18-dependent neutrophil emigration induce upregulation of the ligand, ICAM-l mRNA and protein on endothelial cells while stimuli that elicit CD18-independent emigration do not, suggesting that the regulation of ICAM-l expression determines the selection of adhesion pathway. Because ICAM-l is regulated by cytokines including interleukin-l and tumor necrosis factor-alpha, which adhesion pathway is utilized may be determined by the balance of cytokines produced in response to a particular stimulus. The proposed studies address two questions, what determines whether the CD18-dependent or -independent adhesion pathway is utilized and whether members of the selectin family of adhesion molecules mediate CD18-independent emigration. The working hypotheses are 1) the balance of cytokine production and function in response to a particular stimulus determines which adhesion path way will be utilized, and 2) CD18-independent neutrophil emigration is mediated through selectins. The studies proposed in Aim #1 will determine both the expression of ICAM-l mRNA using Northern blots and in situ hybridization and the function of ICAM-l using ICAM-l deficient mice, anti-sense oligonucleotides, or anti-ICAM-l antibodies by quantitating neutrophil emigration in acute and chronic pneumonia induced by stimuli that elicit either CD18-dependent or -independent emigration, as well as granulomatous inflammation and interstitial fibrosis. The studies proposed in Aim #2 will determine the expression and function of cytokines produced in response to each type of stimulus by measuring the concentrations of pro- adhesive and chemotactic cytokines in the airspaces and by inhibiting their function using either antibodies or soluble receptor-IgG chimera. The expression of E-selectin and its receptor (Aim #3), as well as P- selectin and its receptor (Aim #4) will be localized and quantitated using light and ultrastructural immunohistochemical techniques. The function of these two selectins during acute inflammation will be determined using anti-rabbit E-selectin antibodies, soluble E-selectin-lgG or P-selectin- IgG chimera, and P-selectin-deficient mice. These studies will help to understand the functions of cytokines produced in the lung, the selection of adhesion pathways, and the molecules mediating CD18-independent adhesion. They will investigate new approaches to anti-adhesion molecule and anti-cytokine therapy focussed on increasing leukocyte emigration when it is beneficial and inhibiting this process when it contributes to tissue injury.
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| Gomez, John C; Dang, Hong; Martin, Jessica R et al. (2016) Nrf2 Modulates Host Defense during Streptococcus pneumoniae Pneumonia in Mice. J Immunol 197:2864-79 |
| Gomez, John C; Yamada, Mitsuhiro; Martin, Jessica R et al. (2015) Mechanisms of interferon-? production by neutrophils and its function during Streptococcus pneumoniae pneumonia. Am J Respir Cell Mol Biol 52:349-64 |
| Yamada, Mitsuhiro; Gomez, John C; Chugh, Pauline E et al. (2011) Interferon-? production by neutrophils during bacterial pneumonia in mice. Am J Respir Crit Care Med 183:1391-401 |
| Gomez, John C; Doerschuk, Claire M (2010) The role of CD18 in the production and release of neutrophils from the bone marrow. Lab Invest 90:599-610 |
