Molecular mechanisms of neutrophil and monocyte recruitment in acute lung inflammation
Janardhan, Kyathanahalli Sampath Iyengar
Neutrophils are implicated in many inflammatory lung disorders. However, the mechanisms regulating neutrophil migration in acute lung inflammation are incompletely understood. Although, integrin β2 mediates neutrophil migration in lungs in response to many stimuli such as E. coli, integrin involved in S. pneumoniae induced neutrophil migration is not known. Therefore, the role of integrin αvβ3 in neutrophil recruitment was tested. First, it was found that the number of neutrophils expressing the integrin subunits αv and β3 is reduced or remains in lung inflammation induced by E. coli or S. pneumoniae, respectively. Next, the role of integrin αvβ3 using β3 knockout mice (β3-/-) and function blocking antibodies was addressed. Neutrophil recruitment did not vary between wild type and β3-/- mice. Although β3 antibodies reduced neutrophil recruitment, similar effect was observed with isotype antibodies. Therefore, one can conclude that integrin αvβ3 is not critical for neutrophil recruitment in S. pneumoniae induced pneumonia. Apart from integrins, TLR4 also regulate neutrophil migration. Because, the pattern of TLR4 expression at various times of lung inflammation is not known, TLR4 expression during different phases of lung inflammation in a rat model of LPS-induced inflammation was studied. TLR4 expression in the septum increased and decreased at 6h and 12-36h of inflammation, respectively. Since these correlate with the time of increase and decline of neutrophil recruitment, the findings support previously observed requirement for TLR4 in neutrophil recruitment. Neutrophils recruited into the lungs regulate the inflammatory process by controlling subsequent monocyte/macrophage recruitment. The mechanisms involved and the pattern of monocyte/macrophage recruitment in lungs are not completely understood. Therefore, the possible involvement of monocyte chemoattractant protein (MCP)-1, which is a premier chemokine in monocyte/macrophage migration and produced by neutrophils and other cells was tested. This was addressed by quantification of monocytes/macrophages at various times and using neutrophil depletion experiments in LPS-induced lung inflammation in rats. It was found that monocytes/macrophages migrate very early and before neutrophils in addition to their migration in the late phase of acute lung inflammation. Neutrophil depletion abrogated both early as well as the late monocyte/macrophage recruitment without altering the expression of MCP-1. Therefore, possibly other chemokines and not MCP-1 are involved in neutrophil dependent monocyte/macrophage recruitment. To conclude, the experiments further the understanding on acute lung inflammation by ruling-out the involvement of integrin αvβ3 and MCP-1 in β2-independent neutrophil migration and neutrophil dependent monocyte/macrophage recruitment, respectively. Further studies are essential to find the integrins and chemokines operating in the above situations. Equally important will be to understand the functional significance of early recruited monocytes/macrophages in the lung.
DegreeDoctor of Philosophy (Ph.D.)
DepartmentVeterinary Biomedical Sciences
ProgramVeterinary Biomedical Sciences
CommitteeSharma, Rajendra K.; Misra, Vikram; Hiebert, Linda M.; Hamilton, Donald L.
Copyright DateJune 2006