ENDOGENOUS SUPPRESSION OF LUNG INFLAMMATION
Lead Research Organisation:
University of Edinburgh
Department Name: MRC Centre for Inflammation Research
Abstract
When we breathe, we frequently inhale tiny particles that have potential to injure our lungs, especially bacteria or their components. Remarkably, however, our lungs usually resist this injury and do not develop inflammation, the influx into tissues of white blood cells that are ?licensed to kill? bacteria. This resistance to the induction of inflammation is usually a good thing as white blood cells can be indiscriminate killers, inducing undesirably persistent injury of the healthy lung in various inflammatory lung diseases such as bronchitis. Our work indicates that scavenger cells in the lung are triggered to generate anti-inflammatory, protective responses by a cell surface molecule called ?alpha-v integrin?. The trigger to protective responses is binding to scavenger cell alpha-v integrin of cells undergoing natural cell death or ?apoptosis?. These arise naturally in the lung, but their production is increased by lung injury, pointing to a negative feedback loop in healthy lungs ? inhaled bacteria trigger lung cell death, then binding of dying cells to scavenger cells via alpha-v integrin, and triggering of protective responses. We want to characterise the cellular and molecular mechanisms that constitute this protective system. We hope to uncover new insights into the mechanisms, prevention and treatment of chronic inflammatory lung diseases
Technical Summary
We have new data indicating that when myeloid phagocytes in the lung deploy alpha-v integrin to bind apoptotic cells, subsequent phagocyte responses protect the lung from persistent inflammation threatened by injurious airborne stimuli. We now aim to
(1) confirm preliminary data that in the lung, as already demonstrated in the gut and peritoneum, immunosuppressive myeloid phagocyte clearance of dying cells is indeed disrupted in our recently generated lineage-specific knockout mice lacking alpha-v in the myeloid line;
(2) build on preliminary evidence of enhanced acute bleomycin lung injury in mice with myeloid alpha-v deficiency to investigate whether, as in the gut, there is also an increased propensity for luminal microbial stimuli to induce persistent rather than self-limited inflammation; and
(3) investigate whether recipient mice are protected from microbially-induced lung inflammation by the transfer of immunoregulatory myeloid and lymphoid cells generated by TGFa1-dependent mechanisms engaged by normal clearance of apoptotic cells from lungs injured by microbial stimuli.
These studies will provide important new insights into why the lungs are not normally inflammed despite exposure to inhaled microbial stimuli and what may go wrong when lungs develop persistent inflammation.
(1) confirm preliminary data that in the lung, as already demonstrated in the gut and peritoneum, immunosuppressive myeloid phagocyte clearance of dying cells is indeed disrupted in our recently generated lineage-specific knockout mice lacking alpha-v in the myeloid line;
(2) build on preliminary evidence of enhanced acute bleomycin lung injury in mice with myeloid alpha-v deficiency to investigate whether, as in the gut, there is also an increased propensity for luminal microbial stimuli to induce persistent rather than self-limited inflammation; and
(3) investigate whether recipient mice are protected from microbially-induced lung inflammation by the transfer of immunoregulatory myeloid and lymphoid cells generated by TGFa1-dependent mechanisms engaged by normal clearance of apoptotic cells from lungs injured by microbial stimuli.
These studies will provide important new insights into why the lungs are not normally inflammed despite exposure to inhaled microbial stimuli and what may go wrong when lungs develop persistent inflammation.