Novel role for aldose reductase in mediating acute inflammatory responses in the lung.
Exaggerated inflammatory responses and the resultant increases in alveolar-capillary permeability underlie the pathogenesis of acute lung injury during sepsis. This study examined the functions of aldose reductase (AR) in mediating acute lung inflammation. Transgenic mice expressing human AR (ARTg) were used to study the functions of AR since mice have low intrinsic AR activity. In a mild cecal ligation and puncture model, ARTg mice demonstrated an enhanced AR activity and a greater inflammatory response as evaluated by circulating cytokine levels, neutrophil accumulation in the lungs, and activation of Rho kinase in lung endothelial cells (ECs). Compared with WT lung cells, ARTg lung cells produced more IL-6 and showed augmented JNK activation in response to LPS stimulation ex vivo. In human neutrophils, AR activity was required for fMLP-included CD11b activation and up-regulation, respiratory burst, and shape changes. In human pulmonary microvascular ECs, AR activity was required for TNF-alpha-induced activation of the Rho kinase/MKK4/JNK pathway and IL-6 production, but not p38 activation or ICAM-1 expression. Importantly, AR activity in both human neutrophils and ECs was required for neutrophil adhesion to TNF-alpha-stimulated ECs. These data demonstrate a novel role for AR in regulating the signaling pathways leading to neutrophil-EC adhesion during acute lung inflammation.
Ravindranath
Thyyar M
TM
Department of Surgery, Columbia University, New York, NY 10032, USA.
Mong
Phyllus Y
PY
Ananthakrishnan
Radha
R
Li
Qing
Q
Quadri
Nosirudeen
N
Schmidt
Ann Marie
AM
Ramasamy
Ravichandran
R
Wang
Qin
Q
D055371:Acute Lung Injury / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D000276:Adjuvants, Immunologic / Q000235:genetics / Q000502:physiology; D000449:Aldehyde Reductase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002432:Cecum; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D011677:Punctures; D018805:Sepsis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D016207:Cytokines; D018836:Inflammation Mediators; D000449:Aldehyde Reductase