The role of pulmonary intravascular mononuclear phagocytes in the lung inflammatory response to systemic infection in mice

Certain farm animal species including sheep, pigs, cows and horses, possess specialised immune cells that reside within the blood capillaries of the lung called 'pulmonary intravascular macrophages' (PIM), which are a type of mononuclear phagocyte (immune cells capable of ingesting bacteria or foreign materials). In contrast, humans and laboratory animals such as rabbits, rats and mice do not have them. Species with PIM are more prone than other species to lung inflammation and dysfunction after experimental administration of bacterial toxins, because PIM respond vigorously to blood-borne infectious stimuli by releasing various inflammatory messengers. We hypothesised that in mice and other animals lacking these PIM, monocytes, which are a mobile type of mononuclear phagocyte present in the bloodstream, are rapidly recruited to the blood capillaries of the lung in response to bacterial toxin, and these monocytes, termed 'lung-marginated monocytes', play a key role in enhancing the inflammatory response in the lung capillaries, in a similar fashion to PIM in livestock animals. Using mouse models of whole body inflammation produced by injection of bacterial toxin, as well as a special experimental method of monocyte transfusion between mice with different genetic backgrounds, we propose to investigate: 1) whether marginated monocytes enhance inflammation of the lung capillaries and contribute to the progression of lung injury; 2) the relative impact of such local monocyte-mediated effects in the lung capillaries, as compared to the effects induced directly by circulating blood-borne bacterial toxin, in the progression of lung inflammation and injury; and 3) how a special protein inflammatory messenger called tumour necrosis factor-alpha, which appears to play an important role in various other inflammatory diseases, influences the effects of lung-marginated monocytes on lung inflammation and injury. The proposal would clarify the basic mechanisms of how marginated monocytes work in lung host defence in mice, and provide important information regarding the similarities and differences between the lung immune response in laboratory animals and farm animals. The results may help us to understand how PIM regulate lung infection and inflammation, which at this moment pose a risk to the welfare of livestock animals.

Certain farm animal species including sheep, pigs, cows and horses, possess specialised resident mononuclear phagocytes in the pulmonary vasculature, called 'pulmonary intravascular macrophages' (PIM), whereas laboratory animals and humans do not have them. Species with PIM are more prone than other species to lung dysfunction (pulmonary hypertension and oedema) after single dose administration of bacterial products such as endotoxin, due to the vigorous response of PIM in releasing mediators including pro-inflammatory cytokines. We hypothesised that in mice and other animals which lack these PIM, under certain conditions with systemic bacterial infection, blood monocytes are dynamically recruited to the pulmonary microcirculation in response to endotoxin, and these 'lung-marginated monocytes' play a crucial role in augmenting the pulmonary vascular inflammatory response, in a similar fashion to PIM in livestock animals. Using in vivo mouse models of systemic infection with endotoxaemia as well as adoptive transfer of monocytes between mice with various genetic backgrounds, we propose to investigate: 1) whether marginated monocytes enhance pulmonary microvascular inflammation, contributing to the evolution of lung injury; 2) the relative impact of the local monocyte-mediated endothelial activation, as compared to systemic endothelial activation, on the evolution of lung inflammation and injury; and 3) the role of tumour necrosis factor-alpha signalling in the monocyte-mediated lung inflammation and injury. The proposal would clarify the basic mechanisms of how pulmonary intravascular mononuclear phagocytes work in pulmonary host defence in mice, and provide crucial knowledge of comparative pulmonary immunobiology regarding similarities and differences between laboratory and farm animals. The results may offer insights into the biology of PIM and the regulation of lung infection and inflammation, which currently pose a risk to the welfare of livestock animals.