Overexpression of sICAM-1 in the alveolar epithelial space results in an exaggerated inflammatory response and early death in Gram negative pneumonia.
BACKGROUND
A sizeable body of data demonstrates that membrane ICAM-1 (mICAM-1) plays a significant role in host defense in a site-specific fashion. On the pulmonary vascular endothelium, mICAM-1 is necessary for normal leukocyte recruitment during acute inflammation. On alveolar epithelial cells (AECs), we have shown previously that the presence of normal mICAM-1 is essential for optimal alveolar macrophage (AM) function. We have also shown that ICAM-1 is present in the alveolar space as a soluble protein that is likely produced through cleavage of mICAM-1. Soluble intercellular adhesion molecule-1 (sICAM-1) is abundantly present in the alveolar lining fluid of the normal lung and could be generated by proteolytic cleavage of mICAM-1, which is highly expressed on type I AECs. Although a growing body of data suggesting that intravascular sICAM-1 has functional effects, little is known about sICAM-1 in the alveolus. We hypothesized that sICAM-1 in the alveolar space modulates the innate immune response and alters the response to pulmonary infection.


METHODS
Using the surfactant protein C (SPC) promoter, we developed a transgenic mouse (SPC-sICAM-1) that constitutively overexpresses sICAM-1 in the distal lung, and compared the responses of wild-type and SPC-sICAM-1 mice following intranasal inoculation with K. pneumoniae.


RESULTS
SPC-sICAM-1 mice demonstrated increased mortality and increased systemic dissemination of organisms compared with wild-type mice. We also found that inflammatory responses were significantly increased in SPC-sICAM-1 mice compared with wild-type mice but there were no difference in lung CFU between groups.


CONCLUSIONS
We conclude that alveolar sICAM-1 modulates pulmonary inflammation. Manipulating ICAM-1 interactions therapeutically may modulate the host response to Gram negative pulmonary infections.
Division of Pulmonary and Critical Care Medicine, Henry Ford Health System, 2799 West Grand Boulevard, Detroit 48202, USA. mmendez2@hfhs.org
Michael P
MP
Mendez
Yeni K
YK
Monroy
Ming
M
Du
Angela M
AM
Preston
Leslie
L
Tolle
Yujing
Y
Lin
Kelli L
KL
VanDussen
Linda C
LC
Samuelson
Theodore J
TJ
Standiford
Jeffery L
JL
Curtis
James M
JM
Beck
Paul J
PJ
Christensen
Robert
R
Paine
D000178:Acrylamides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D002633:Chemotaxis; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology* / Q000382:microbiology; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D007710:Klebsiella Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000472:pathogenicity*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010587:Phagocytosis; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli / Q000276:immunology* / Q000382:microbiology; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism
C531963:2-(2,6-dichloro-4-((3-furan-2-ylacryloylamino)methyl)benzoylamino)-3-((thiazolidine-4-carbonyl)amino)propionic acid; D000178:Acrylamides; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D018836:Inflammation Mediators; D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human; D014409:Tumor Necrosis Factor-alpha; D015091:beta-Alanine
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