UAB Department of Medicine Research Portal

Mol. Endocrinology2008 Mar 6.
Endotoxin-Induced Proteolytic Reduction in Hepatic Growth Hormone Receptor: A Novel Mechanism for GH Insensitivity.
Wang X, Jiang J, Warram J, Baumann G, Gan Y, Menon RK, Denson LA, Zinn KR, Frank SJ.

Abstract:Growth hormone (GH) is an important anabolic hormone. We previously demonstrated in cell culture that the cell surface GH receptor (GHR) is susceptible to inducible metalloproteolytic cleavage that yields the shed receptor extracellular domain (called GHBP) and renders the cells desensitized to subsequent GH stimulation. Sepsis and inflammatory states are associated with hepatic desensitization to GH, although disparate mechanisms have been postulated in various animal models. Using C3H/HeJ mice, we now demonstrate that administration of lipopolysaccharide (LPS) causes marked hepatic desensitization to GH, assessed by monitoring STAT5 tyrosine phosphorylation and nuclear accumulation and with a novel noninvasive bioluminescence imaging system to track in vivo hepatic GH signaling serially in individual mice. This endotoxin-induced desensitization was accompanied by marked loss of hepatic GHR, which was not explained by changes in GHR mRNA abundance. Furthermore, we observe that LPS causes GHBP shedding of a hepatically expressed wild-type GHR, but not a GHR with a mutation in the metalloprotease cleavage site. These data suggest that in this model system, LPS-induced desensitization to GH is associated with proteolytic GHR cleavage. These data are the first to demonstrate inducible in vivo GHR proteolysis and suggest that this is a mechanism to regulate GH sensitivity and its anabolic effects during sepsis or inflammation.

J Exp Med. 2007 Mar 19:204(3):605-18
Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism.
Deshane J, Chen S, Caballero S, Grochot-Przeczek A, Was H, Li Caizi S, Lach R, Hock TD, Chen B, Hill-Kaptruczak N, Siegal GP, Dulak J, Jozkowicz A, Grant MB, Agarwal A.

Abstract:Stromal cell-derived factor 1 (SDF-1) plays a major role in the migration, recruitment, and retention of endothelial progenitor cells to sites of ischemic injury and contributes to neovascularization. We provide direct evidence demonstrating an important role for heme oxygenase 1 (HO-1) in mediating the proangiogenic effects of SDF-1. Nanomolar concentrations of SDF-1 induced HO-1 in endothelial cells through a protein kinase C zeta-dependent and vascular endothelial growth factor-independent mechanism. SDF-1-induced endothelial tube formation and migration was impaired in HO-1-deficient cells. Aortic rings from HO-1(-/-) mice were unable to form capillary sprouts in response to SDF-1, a defect reversed by CO, a byproduct of the HO-1 reaction. Phosphorylation of vasodilator-stimulated phosphoprotein was impaired in HO-1(-/-) cells, an event that was restored by CO. The functional significance of HO-1 in the proangiogenic effects of SDF-1 was confirmed in Matrigel plug, wound healing, and retinal ischemia models in vivo. The absence of HO-1 was associated with impaired wound healing. Intravitreal adoptive transfer of HO-1-deficient endothelial precursors showed defective homing and reendothelialization of the retinal vasculature compared with HO-1 wild-type cells following ischemia. These findings demonstrate a mechanistic role for HO-1 in SDF-1-mediated angiogenesis and provide new avenues for therapeutic approaches in vascular repair.

Annu Rev Immunol.2007;25:525-60 (Full Text | PDF )
Fc receptor-like molecules.
Davis RS.

Abstract: Discovery of a large family of Fc receptor-like (FCRL) molecules, homologous to the well-known receptors for the Fc portion of immunoglobulin (FCR), has uncovered an impressive abundance of immunoglobulin superfamily (IgSF) genes in the human 1q21-23 chromosomal region and revealed significant diversity for these genes between humans and mice.The observation that FCRL representatives are members of an ancient multigene family that share a common ancestor with the classical FCR is underscored by their linked genomic locations, gene structure, shared extracellular domain composition, and utilization of common cytoplasmic tyrosine-based signaling elements.In contrast to the conventional FCR, however, FCRL molecules possess diverse extracellular frameworks, autonomous or dual signaling properties, and preferential B lineage expression.Most importantly, there is no strong evidence thus far to support a role for them as Ig-binding receptors.These characteristics, in addition to their identification in malignancies and autoimmune disorders, predict a fundamental role for these receptors as immunomodulatory agents in normal and subverted B lineage cells.

Hepatology. 2008 Apr;47(4):1257-63.
Oxygen desaturation during sleep in hepatopulmonary syndrome.
Palma DT, Philips GM, Arguedas MR, Harding SM, Fallon MB.

Abstract: Sleep alters respiratory mechanics and gas exchange, which can adversely affect arterial oxygenation. Whether sleep affects oxygenation in hepatopulmonary syndrome is unknown. The aim of this study was to assess oxygen desaturation during sleep in hepatopulmonary syndrome. Twenty adults with cirrhosis including 10 controls and 10 patients with hepatopulmonary syndrome underwent home pulse-oximetry during sleep. Subjects at high risk for obstructive sleep apnea were excluded through the Berlin questionnaire. Subjects who spent more than 10% of total sleep time with arterial oxygen saturation < 90% were classified as sleep-time oxygen desaturators. Sleep-time desaturation was correlated with clinical variables. The results showed that 7 of 10 hepatopulmonary syndrome subjects and none of the 10 controls had sleep-time oxygen desaturation. The median percentage of total sleep time with arterial oxygen saturation < 90% was significantly higher in hepatopulmonary syndrome subjects than in controls (medians 25% versus 0%, P = 0.005). Hepatopulmonary syndrome subjects had significantly lower wake-time arterial oxygen saturation level (median, 97% versus 95%; P = 0.003) and mean sleep-time arterial oxygen saturation level (median, 96% versus 91%; P = 0.0008) than did the controls. Sleep-time desaturation directly correlated with alveolar-arterial oxygen gradient (P = 0.0007) and inversely correlated with wake-time arterial oxygen tension (P = 0.0007) and oxygen saturation (P < 0.0001). Conclusion: Oxygen desaturation occurred during sleep in 70% of hepatopulmonary syndrome subjects, the degree of which correlated with the severity of hepatopulmonary syndrome. Marked hypoxemia during sleep may occur in hepatopulmonary syndrome patients who, according to wake-time oxygen values, have only mild to moderate hypoxemia.

Kidney Int.2008 Jan;73(1):63-76.
Overexpression of innate immune response genes in a model of recessive polycystic kidney disease.
Mrug M, Zhou J, Woo Y, Cui X, Szalai AJ, Novak J, Churchill GA, Guay-Woodford LM.

Abstract:Defects in the primary cilium/basal body complex of renal tubular cells cause polycystic kidney disease (PKD). To uncover pathways associated with disease progression, we determined the kidney transcriptome of 10-day-old severely and mildly affected cpk mice, a model of recessive PKD. In the severe phenotype, the most highly expressed genes were those associated with the innate immune response including many macrophage markers, particularly those associated with a profibrotic alternative activation pathway. Additionally, gene expression of macrophage activators was dominated by the complement system factors including the central complement component 3. Additional studies confirmed increased complement component 3 protein levels in both cystic and non-cystic epithelia in the kidneys of cpk compared to wild-type mice. We also found elevated complement component 3 activation in two other mouse-recessive models and human-recessive PKD. Our results suggest that abnormal complement component 3 activation is a key element of progression in PKD.