OUR RESEARCH
Our laboratory primarily investigates infectious and inflammatory processes, with a special emphasis on the underpinnings of preterm labor. Premature birth is the major cause of neonatal morbidity and mortality in the developed world, accounting for at least 75% of neonatal deaths that are not due to congenital malformations. We seek to elucidate the processes by which intrauterine or systemic bacterial infections and/or inflammatory states in pregnancy result in preterm delivery. Infection is thought to be the cause of up to 40% of cases of preterm birth, including many ‘idiopathic’ or unexplained cases. We hope these studies result in novel methods to prevent preterm birth.
CURRENT RESEARCH INTERESTS
The powerful anti-labor effect of a fetally produced protein known as surfactant protein A (SP-A).
Agrawal V, Jaiswal MK, Beaman KD and Hirsch E. Surfactant Protein (SP)-A Suppresses Preterm Delivery Induced by Live E. coli in Mice. Biol Reprod (2018) 99:546-555 doi: 10.1093/biolre/ioy074. PMID: 29590302.
Agrawal V, Smart K, Jilling T, Hirsch E. Surfactant Protein (SP)-A Suppresses Preterm Delivery and Inflammation via TLR2. PLoS ONE (2013) 8 (5):e63390. DOI: 10.1371/journal.pone.0063990. PMID:23700442.
In the clinical realm we are interested in enhancing the achievement of safe vaginal delivery (avoidance of cesarean section and of maternal injury to the tissues of the perineum).
Scholz RC, Smith BA, Adams MG, Shah M, Brudner C, Datta A, Hirsch E. A multi-faceted surgical site infection prevention bundle for cesarean delivery. Am J Perinatol (2019) Epub ahead of print. doi: 10.1055/s-0039-3400993.
Hirsch E, Elue R, Wagner A, Nelson K, Silver RK, Zhou Y, Adams MG. Severe perineal laceration during operative vaginal delivery: the impact of occiput posterior position. J Perinatol (2014) 34:898-900. doi: 10.1038/jp.2014.103. Epub 2014 May 29.
The overlap between infection, sterile inflammation and other causes of preterm labor.
Agrawal V, Jaiswal MK, Mallers T, Gilman-Sachs A, Beaman KD, Hirsch E. Altered autophagic flux enhances inflammatory responses during inflammation-induced preterm labor. Sci Rep (2015) 5:9410. doi: 10.1038/srep09410
The association between maternal viral infection and preterm labor.
In this analysis, we report that among patients presenting to the hospital with an initiating event of labor… the prevalence of circulating anellovirus… is higher in preterm than in term patients. … [A]nelloviruses might affect the onset of labor through alteration of the inflammatory and immune landscape, lowering the threshold for a labor response to stimuli, such as subclinical bacterial infection, that on their own would be insufficient to induce parturition.
Shah AA, Wang, D, Hirsch E. Nucleic acid-based screening of maternal serum to detect viruses in women with labor or PROM. Reproductive Sciences. 2020 Jan 10 Epub ahead of print. doi: 10.1007/s43032-019-00051-2.
PREVIOUS SCIENTIFIC CONTRIBUTIONS
Data from the lab were the first to use high-throughput methods to identify genes associated with preterm delivery.
Muhle RA, Pavlidis P, Grundy WN, Hirsch E. A high throughput study of gene expression in preterm labor with a subtractive microarray approach. Am J Obstet Gynecol (2001) 185:716-724.
Interleukin (IL-) 1 is not an essential mediator of bacterially induced preterm labor, although it plays a necessary overlapping role with TNF.
Hirsch E, Muhle RA, Mussalli GM, Blanchard R. Bacterially induced preterm labor in the mouse does not require maternal interleukin 1 signaling. Am J Obstet Gynecol (2002) 186:523-530.
Yoshimura K and Hirsch E. Effect of stimulation and antagonism of interleukin-1 signaling on preterm delivery in mice. J Soc Gynecol Invest (2005) 12:533-8.
Hirsch E, Filipovich Y, Mahendroo M. Signaling via the type I IL-1 and TNF receptors is necessary for bacterially induced preterm labor in a murine model. Am J Obstet Gynecol (2006) 194:1334-40.
Prostaglandins (central mediators of inflammatory labor) are regulated via altered degradation rather than altered production.
Wang H and Hirsch E. Bacterially induced preterm labor and regulation of prostaglandin metabolizing enzyme expression in mice: the role of toll-like receptor 4. Biol Reprod (2003) 69:1957-63.
Hirsch E, Goldstein M, Filipovich Y, Wang H. Placental expression of enzymes regulating prostaglandin synthesis and degradation. Am J Obstet Gynecol (2005) 192:1836-43.
E. coli-induced preterm delivery in the mouse is a process not dependent upon progesterone withdrawal but is mediated by toll-like receptor (TLR) 4, with complete dependence on the TLR adaptor protein, MyD88.
Hirsch E, Muhle RA. Intrauterine bacterial inoculation induces labor in the mouse by mechanisms other than progesterone withdrawal. Biol Reprod (2002) 67:1337-1341.
Filipovich Y, Lu S-J, Akira S, Hirsch E. The adaptor protein MyD88 is essential for E. coli induced preterm delivery in mice. Am J Obstet Gynecol (2009) 200:93.e1-93.e8.
There is synergy in the activation of inflammatory pathways and labor when TLR3 and TLR2 are engaged simultaneously. We hypothesize that the existence of this synergy is a mechanism by which labor responses are blunted in the face of insults of limited significance and are amplified in response to insults of a greater magnitude (a “two hit” mechanism).
Ilievski V, Lu S-J, Hirsch E. Activation of toll-like receptors (TLR) -2 or -3 and preterm delivery in the mouse. Reproductive Sciences (2007) 14: 315-320.
Ilievski V and Hirsch E. Synergy between viral and bacterial toll-like receptors leads to amplification of inflammatory responses and preterm labor in the mouse. Biol Reprod (2010) 83:767-773, doi:10.1095/biolreprod.110.085464.
Together with our collaborators at Rosalind Franklin University of Medicine and Science we have characterized roles during labor for apoptosis , platelet activating factor (PAF), autophagy, Notch signaling, and IL-22.
Jaiswal MK, Agrawal V, Mallers T, Gilman-Sachs A, Hirsch E and Beaman KD. Regulation of Apoptosis and Innate Immune Stimuli in Inflammation Induced Preterm Labor. J Immunol (2013) 191:5702-13. PMID:24163412.
Agrawal V, Jaiswal MK, Ilievski V, Beaman KD, Jilling T, Hirsch E. Platelet Activating Factor (PAF): A role in preterm delivery and an essential interaction with toll-like receptor (TLR) signaling in mice. Biol Reprod (2014) Nov;91(5):119. DOI: 10.1095/biolreprod.113.116012.
Jaiswal MK*, Agrawal V*, Pamarthy S, Katara GK, Kulshrestha A, Gilman-Sachs A, Beaman KD and Hirsch E (*co-first authors). Notch signaling in inflammation-induced preterm labor. Sci Rep. 2015 Oct 16;5:15221. doi: 10.1038/srep15221. PMID: 26472156
Agrawal V*, Jaiswal MK*, Pamarthy S, Katara G, Kulshrestha A, Gilman-Sachs A, Hirsch E, Beaman KD (*co-first authors). Role of Notch signaling during lipopolysaccharide-induced preterm labor. J Leukoc Biol. (2016) 100:261-74 doi: 10.1189/jlb.3HI0515-200RR. PMID: 26373439.
Featured as “Leading Edge Research” with a press release on the FASEB website
Dambaeva S, Schneiderman S, Jaiswal MK, Agrawal V, Katara G, Gilman-Sachs A, Hirsch E, Beaman KD. IL-22 Prevents Lipopolysaccharide-Induced Preterm Labor in Mice. Biol Reprod (2018) 98:299-308. doi: 10.1093/biolre/iox182. PMID: 29315356.
Depletion of polymorphonuclear leukocytes (PMNs, white cells responsible for coordinating inflammatory responses) does not prevent preterm delivery in the mouse infection model.
Filipovich Y, Agrawal V, Crawford SE, Fitchev P, Qu X, Klein J; Hirsch E. Depletion of polymorphonuclear leukocytes has no effect on preterm delivery in a mouse model of E. coli-induced labor. Am J Obstet Gynecol. (2015) 213:697.e1-10. doi: 10.1016/j.ajog.2015.07.025. PMID: 26215328.
Preterm delivery in the mouse inflammation model is completely dependent upon the mother with no demonstrable fetal role.
Filipovich, Y, Klein J, Zhou Y, Hirsch E. Maternal and fetal roles in bacterially-induced preterm labor in the mouse. Am J Obstet Gynecol (2016) 214:386.e1-9. doi: 10.1016/j.ajog.2015.10.014. PMID: 26478101.
TLR agonists decrease both lysosome function and autolysosome formation (two key processes in autophagy, a process by which cellular components are recycled, and the subject of the 2016 Nobel Prize in Physiology or Medicine), which supresses autophagy and leads to hyperinflammation and preterm labor.
Agrawal V, Jaiswal MK, Mallers T, Gilman-Sachs A, Beaman KD, Hirsch E. Altered autophagic flux enhances inflammatory responses during inflammation-induced preterm labor. Sci Rep (2015) 5:9410. doi: 10.1038/srep09410
Modulation of interleukin (IL-) 1 inflammatory signaling by an endogenous antagonist of its receptor has implications for treatment of inflammation, infection, and associated conditions, including preterm delivery, atherosclerosis, arthritis, and Alzheimer's disease.
Hirsch E, Irikura VM, Paul SM, Hirsh D. Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci USA (1996) 93:11008-13.
Ma Y, Thornton S, Boivin GP, Hirsh D, Hirsch R, Hirsch E. Altered susceptibility to collagen induced arthritis in transgenic mice with aberrant expression of IL-1 receptor antagonist. Arthritis Rheum (1998) 41: 1798-1805.
Irikura VM, Hirsch E, Hirsh D. Effects of interleukin 1 receptor antagonist overexpression on infection by Listeria monocytogenes. Infect Immun (1999) 67: 1901-1909.
Josephs MD, Solorzano CC, Ksontini R, Taylor M, Topping D, Abouhamze A, Mackay SLD, Hirsch E, Hirsh D, Labow M, Moldawer LL. Modulation of the acute phase response by altered expression of the IL-1 type 1 receptor or IL-1ra. Am J Physiol Regul Integr Comp Physiol (2000) 278:R824-R830.
Devlin CM, Kuriakose G, Hirsch E, Tabas I. Genetic alterations of interleukin-1 receptor antagonist in mice markedly affect non-HDL lipoprotein cholesterol levels and foam cell lesion size. Proc Natl Acad Sci USA (2002) 99:6280-6285.
The mouse model of preterm delivery we developed is widely used around the world to study preterm labor.
Hirsch E, Saotome I, Hirsh D. A model of intrauterine infection and preterm delivery in mice. Am J Obstet Gynecol (1995) 172:1598-603.
Hirsch E, Mehta SP, Blanchard RK. Differential fetal and maternal contributions to the cytokine milieu in a murine model of infection-induced preterm birth. Am J Obstet Gynecol (1999) 180(2 Pt 1): 429-434
Mussalli GM, Blanchard RK, Brunnert SR, Hirsch E. Inflammatory cytokines in a murine model of infection-induced preterm labor: Cause or effect? J Soc Gynecol Invest (1999) 6:188-195