Johns Hopkins University

Roger A Johns

Yuanxiang Tao

Dechun Li

Xingwu Teng

Hunter Clay Champion

Qingning Su

The present invention relates to the field of pulmonary, cardiac and inflammatory disorders. More specifically, the present invention provides methods and compositions for treating disorders associated with Resistin. In a specific embodiment, the present invention provides an antibody that binds human Resistin.

Method for treating pulmonary hypertension with antibodies to human Resistin

Antibodies to human resistin

We found that FIZZ1/RELM&#x3b1; is inducible by hypoxia in lung. The hypoxia-upregulated expression of FIZZ1/RELM&#x3b1; was located in the pulmonary vasculature, bronchial epithelial cells, and type II pneumocytes. Recombinant FIZZ1/RELM&#x3b1; protein stimulates rat pulmonary microvascular smooth muscle cell (RPSM) proliferation dose-dependently. Therefore, we renamed this gene as hypoxia-induced mitogenic factor (HIMF). HIMF strongly activated Akt phosphorylation. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 inhibits HIMF-activated Akt phosphorylation. It also inhibits HIMF-stimulated RPSM proliferation. Thus, the PI3K/Akt pathway, at least in part, mediates the proliferative effect of HIMF. HIMF also has angiogenic and vasoconstrictive activity. Notably, HIMF increases pulmonary arterial pressure and vascular resistance more potently than either endothelin-1 or angiotensin II.

Method of promoting wound healing with hyodxia-induced mitogenic factor

Method for treating pulmonary hypertension

Hypoxia induced mitogenic factor (HIMF) is a member of the 'found in inflammatory zone' (FIZZ)/resistin family of proteins and has potent mitogenic, angiogenic, and vasoconstrictive effects in the lung vasculature. We use antibodies to HIMF to treat certain diseases including adult respiratory distress syndrome, radiation-induced pulmonary fibrosis, idiopathic pulmonary fibrosis, and emphysema.

Anti-HIMF antibodies to treat lung diseases

Method of treating hypertrophic cardiomyopathy

PSD-95/SAP90 antisense-treated animals not only experience a significant decrease in MAC for isoflurane, but also experience an attenuation in the NMDA-induced increase in isoflurane MAC. PSD-95/SAP90 appears to mediate the role of the NMDA receptor in determining the MAC of inhalational anesthetics. Suppression of the expression of PSD-95/SAP90 in the spinal cord significantly attenuates responses to painful stimuli mediated through the N-methyl-D-aspartate receptor activation. In spinal cord neurons PSD-95/SAP90 interacts with the N-methyl-D-aspartate receptor subunits 2A/2B. Activation of the N-methyl-D-aspartate receptor in spinal hyperalgesia results in association of the N-methyl-D-aspartate receptor with PSD-95/SAP90. PSD-95/SAP90 is required for hyperalgesia triggered via the N-methyl-D-aspartate receptor at the spinal cord level.

Inhibition of interaction of PSD93 and PSDS95 with nNOS and NMDA receptors

Hypoxia induced mitogenic factor

Inhibition of interaction of PSD93 and PSD95 with nNOS and NMDA receptors

Several lines of evidence have shown a role for the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway in the development of spinal hyperalgesia. However, the roles of effectors for cGMP are not fully understood in the processing of pain in the spinal cord. cGMP-dependent protein kinase (PKG) I&#x3b1; but not PKGI&#x3b2; was localized in the neuronal bodies and processes, and was distributed primarily in the superficial laminae of the spinal cord. Intrathecal administration of an inhibitor of PKGI&#x3b1;, Rp-8-[(4-Chlorophenyl)thio]-cGMPS triethylamine, produces significant antinociception. Moreover, PKGI&#x3b1; protein expression was dramatically increased in the lumbar spinal cord after noxious stimulation. This upregulation of PKGI&#x3b1; expression was completely blocked not only by a neuronal NO synthase inhibitor, and a soluble guanylate cyclase inhibitor, but also by an N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. Noxious stimulation not only initially activates but also later upregulates PKGI&#x3b1; expression in the superficial laminae via an NMDA-No-cGMP signaling pathway, suggesting that PKGI&#x3b1; plays an important role in the central mechanism of inflammatory hyperalgesia in the spinal cord.

Isoform specific inhibition for treatment of pain and reduction of anesthetic threshold

Several lines of evidence have shown a role for the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway in the development of spinal hyperalgesia. However, the roles of effectors for cGMP are not fully understood in the processing of pain in the spinal cord. cGMP-dependent protein kinase (PKG) I&#x3b1; but not PKGI&#x3b2; was localized in the neuronal bodies and processes, and was distributed primarily in the superficial laminae of the spinal cord. Intrathecal administration of an inhibitor of PKGI&#x3b1;, Rp-8-[(4-Chlorophenyl)thio]-cGMPS triethylamine, produces significant antinociception. Moreover, PKGI&#x3b1; protein expression was dramatically increased in the lumbar spinal cord after noxious stimulation. This upregulation of PKGI&#x3b1; expression was completely blocked not only by a neuronal NO synthase inhibitor, and a soluble guanylate cyclase inhibitor, but also by an N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. Noxious stimulation not only initially activates but also later upregulates PKGI&#x3b1; expression in the superficial laminae via an NMDA-NO-cGMP signaling pathway, suggesting that PKGI&#x3b1; plays an important role in the central mechanism of inflammatory hyperalgesia in the spinal cord.

Several lines of evidence have shown a role for the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway in the development of spinal hyperalgesia. However, the roles of effectors for cGMP are not fully understood in the processing of pain in the spinal cord. cGMP-dependent protein kinase (PKG) I&agr; but not PKGI&bgr; was localized in the neuronal bodies and processes, and was distributed primarily in the superficial laminae of the spinal cord. Intrathecal administration of an inhibitor of PKGI&agr;, Rp-8-&lsqb;(4-Chlorophenyl)thio&rsqb;-cGMPS triethylamine, produces significant antinociception. Moreover, PKGI&agr; protein expression was dramatically increased in the lumbar spinal cord after noxious stimulation. This upregulation of PKGI&agr; expression was completely blocked not only by a neuronal NO synthase inhibitor, and a soluble guanylate cyclase inhibitor, but also by an N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. Noxious stimulation not only initially activates but also later upregulates PKGI&agr; expression in the superficial laminae via an NMDA-NO-cGMP signaling pathway, suggesting that PKGI&agr; plays an important role in the central mechanism of inflammatory hyperalgesia in the spinal cord.

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Reisterstown, MD, United States of America

Roger A Johns