Biology subjects

Saigal, A.

Publications and source records attributed to Saigal, A..

3 recordsLinked to original sources

bioRxiv2020

Discovery of A New Class of Integrin Antibodies for Fibrosis

Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of all v integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimabs yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple v integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGF{beta} activation. In IPF patient lung fibroblasts, TGF{beta} treatment induced profound SMA expression in phenotypic imaging assays and Ab-31 demonstrated superior in vitro activity at inhibiting SMA expression, suggesting that the integrin antibody is able to modulate TGF{beta} action though mechanisms beyond the inhibition of latent TGF{beta} activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases. One Sentence Summarytargeting integrin in lung fibrosis

pharmacology and toxicology↗

bioRxiv2020

Identification of the Molecular Basis of Anti-fibrotic Effects of Soluble Guanylate Cyclase Activator Using the Human Lung Fibroblast Phosphoproteome

Idiopathic pulmonary fibrosis (IPF) is an irreversible and progressive fibrotic lung disease. Advanced IPF patients often demonstrate pulmonary hypertension, which severely impairs patients quality of life. The critical physiological roles of soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway have been well characterized in vasodilation and the corresponding therapies and pathway agonists have shown clinical benefits in treating hypertension. In recent years, many preclinical studies have demonstrated anti-fibrotic efficacy of sGC-cGMP activation in various experimental fibrosis models but the molecular basis of the efficacy in these models are not well understood. Also, sGC pathway agonism has demonstrated encouraging clinical benefits in advanced IPF patients (NCT00517933). Here, we have revealed the novel phosphorylation events downstream of sGC activation in human lung fibroblasts using phosphoproteomics. sGCact A, a potent and selective sGC activator, significantly attenuated more than 2,000 phosphorylation sites. About 20% of phosphorylation events, attenuated by transforming growth factor {beta} (TGF{beta}), a master regulator of fibrosis, were further dysregulated in the sGCact A co-treated lung fibroblasts. The overall magnitude and diversity of the sGCact A phosphoproteome was extensive. Further investigation would be required to understand how these newly identified changes facilitate human pulmonary fibrosis.

molecular biology↗

bioRxiv2020

Myeloid cell mPGES-1 mediates inflammatory pain hypersensitivity in mice.

Nonsteroidal anti-inflammatory drugs (NSAIDs) relieve inflammatory pain by predominant suppression of cyclooxygenase-2 derived prostaglandin (PG) E2. Innate immune cells contribute to inflammatory pain hypersensitivity and may be an attractive target for novel non-addictive approaches to pain management. We studied the contribution of PGE2 produced by myeloid cell microsomal prostaglandin E synthase -1 (mPGES-1) to peripheral inflammation and hyperalgesia in mice. Selective deletion of mPGES-1 in myeloid cells by crossing LysM-Cre mice with mPGES-1flox/flox mice (Mac-mPGES-1-KO) resulted in significantly reduced mechanical and thermal hyperalgesia in complete Freunds adjuvant (CFA)-evoked hind paw inflammation, zymosan-induced peri-articular inflammation and collagen II antibody-induced arthritis models. Systemic COX-2 inhibition or myeloid cell specific COX-2 deletion (by crossing LysM-Cre with COX-2 flox/flox mice) recapitulated reduction of CFA-induced inflammation and hyperalgesia. In contrast, deletion of mPGES-1 in neurons and glial cells by crossing mPGES-1flox/flox mice with Nestin-Cre mice had no detectable effect on inflammatory pain hypersensitivity. While macrophage recruitment was unaltered, tissue concentrations of PGE2, IL-1{beta} and TNF were significantly reduced in Mac-mPGES-1-KO paw tissues following CFA induction. Our results demonstrate that myeloid cell mPGES-1 is the dominant source of PGE2 in inflammatory pain hypersensitivity. Targeting myeloid cell mPGES-1 may afford a novel approach to inflammatory pain therapy.

pharmacology and toxicology↗