Pathophysiologic role of alpha 4 integrins in the lung.
Evidence for a central role for the integrins alpha 4 beta 1 and alpha 4 beta 7 in leukocyte pathophysiology is rapidly accumulating. Five distinct alpha 4 mAbs, each able to block alpha 4-dependent adhesion in vitro, show beneficial effects in vivo in six different species, and in a wide variety of organ systems, including colon, lung, skin, neural tissue, pancreas, peritoneum, and the vessel wall. In particular, a clear role for these integrins in lung pathophysiology is implied on the basis of in vivo studies in four different species. Although several issues remain to be resolved, including the relative importance of alpha 4 beta 1 and alpha 4 beta 7, and the relative roles of their counterligands, VCAM1, fibronectin, and MAdCAM, the data argue that alpha 4 integrins will likely be critical to both the normal physiology and pathology of the lung in man. To this end, we (Adams, Lin, Lobb, and Gill, unpublished data) and others have generated peptidomimetic small molecule antagonists of VLA4 based on the connecting segment 1 (CS1) peptide sequence of fibronectin that are potent blockers of integrin adhesive function in vitro and show efficacy in vivo. We have found that our inhibitors are excellent blockers of both murine contact hypersensitivity, and of the LPR and AHR in the sheep allergic airways model (Abraham, Lobb, Adams, and Gill, unpublished data), and are therefore possible candidates for clinical intervention in human asthma. The use of the VCAM-Ig fusion protein as a probe for high-affinity alpha 4 integrins has further enhanced our understanding of alpha 4 integrin function in the lung. While integrin upregulation in vitro has been observed many times, and high affinity (as opposed to avidity) of integrins seen in vitro in several systems, in vivo proof of integrin upregulation to a high-affinity state has been difficult to obtain in the absence of selective probes. Our data provide key information in this regard and strongly argue not only that integrin upregulation does indeed occur in vivo, but also that it is in fact obligatory for the leukocyte pathologies we have examined to date. Further studies are clearly warranted to further examine mechanisms of action, and to confirm and extend these studies, both with the alpha 4 integrins and with other integrin families. In summary, our studies of alpha 4 integrins continue to provide novel insights into the pathophysiology of integrin function and into future directions for drug discovery.
Lobb
R R
RR
Biogen, Inc., Cambridge, Massachusetts 02142, USA.
Abraham
W M
WM
Burkly
L C
LC
Gill
A
A
Ma
W
W
Knight
J A
JA
Leone
D R
DR
Antognetti
G
G
Pepinsky
R B
RB
D000818:Animals; D001249:Asthma / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology*; D008168:Lung / Q000503:physiopathology*; D008297:Male; D051379:Mice; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012756:Sheep; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology
D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7