Patricia A Hebda

University of Pittsburgh | Pitt · Plastic Surgery, Pathology

Purpose of review: Injured skin in the mammalian fetus can heal regeneratively due to the ability of fetal fibroblasts to effectively reorganize the extracellular matrix (ECM). This process occurs without fetal fibroblasts differentiating into highly contractile myofibroblasts which cause scarring and fibrosis in adult wounds. Here, we provide a b...

Steroids are used for the treatment of laryngitis in vocal performers and other individuals despite the absence of evidence demonstrating their impact on vocal fold inflammation. Our objective was to examine laryngeal secretion cytokine inflammatory profile changes associated with corticosteroid treatment in a human phonotrauma model. Prospective,...

Provided are methods of simulating tissue healing. The methods comprise using a mechanistic computer model of the interrelated effects of inflammation, tissue damage or dysfunction and tissue healing to predict an outcome of healing of damaged tissue in vivo, thereby predicting the outcome of healing of damaged tissue in vivo. Implementations of th...

The adverse physiological and psychological effects of scars formation after healing of wounds are broad and a major medical problem for patients. In utero, fetal wounds heal in a regenerative manner, though the mechanisms are unknown. Differences in fetal scarless regeneration and adult repair can provide key insight into reduction of scarring the...

The objective was to assess the utility of selected "resonant voice" (RV) exercises for the reduction of acute vocal fold inflammation. The hypothesis was that relatively large-amplitude, low-impact vocal fold exercises associated with RV would reduce inflammation more than spontaneous speech (SS) and possibly more than voice rest. The study design...

Objective To evaluate the role of targeted cyclooxygenase-2 inhibition in reducing scarring associated with a subglottic airway mucosal injury. Design Thirty-four New Zealand white rabbits underwent anterior cricothyroidotomy. Subglottic stenosis (SGS) was created by carbon dioxide laser injury. Intervention Treatment consisted of intraperitoneal i...

Tympanostomy tube otorrhea (TTO), caused by the presence of pathogenic bacteria in the middle ear, is the most common complication of TT insertion. No studies have described a reproducible animal model of TTO. We aimed to develop a rat model of TTO which, in turn, could be used to assay the levels of TNF-α and IL-1β through the course of the infect...

Personalized, preemptive, and predictive medicine is a central goal of contemporary medical care. The central aim of the present study was to investigate the utility of mechanistic computational modeling of inflammation and healing to address personalized therapy for patients with acute phonotrauma. Computer simulation. Previously reported agent-ba...

The pathogenesis of vocal fold scarring is complex and remains to be deciphered. The current study is part of research endeavors aimed at applying systems biology approaches to address the complex biological processes involved in the pathogenesis of vocal fold scarring and other lesions affecting the larynx. We developed a computational agent-based...

Personalized medicine has been called upon to tailor healthcare to an individual's needs. Evidence-based medicine (EBM) has advocated using randomized clinical trials with large populations to evaluate treatment effects. However, due to large variations across patients, the results are likely not to apply to an individual patient. We suggest that a...

To investigate the association between mucosal fibroblast activity and subglottic stenosis (SGS) development. Prospective study of an animal model of SGS. Academic research laboratory. New Zealand white rabbits were assigned to either the cricothyroidotomy and carbon dioxide laser injury group or the cricothyroidotomy and silver nitrate injury grou...

To characterize the activation of cyclooxygenase (COX)-2/prostaglandin (PG) E2 signaling during airway mucosal repair and its subsequent role during the wound healing process. Prospective animal study. The subglottis was approached via cricothyroidotomy. Sham airways were closed, and wounded airways were subjected to laser injury and closed. Subglo...

To test urinary bladder matrix (UBM) as a potential treatment for tympanic membrane (TM) healing and regeneration. This prospective pilot study was designed to provide both qualitative and semiquantitative assessment of temporal and spatial healing events in the chinchilla model of chronic TM perforations with and without UBM patching. Bilateral my...

Wound healing is a complex, orchestrated series of biological events that is controlled by extracellular components that communicate between cell types to re-establish lost tissue. We have found that signaling by ELR-negative CXC chemokines through their common CXCR3 receptor is critical for dermal maturation during the resolving phase. In addition...

Contraction and remodeling of granulation tissue by fibroblasts is a crucial component of dermal wound healing. Postnatal wounds heal with imperfect repair and scar formation, whereas tissue repair in fetal wounds is regenerative. Prostaglandin E2 (PGE2) modulates the behavior of fibroblasts in the wound bed. This study was designed to investigate...

Normal adult wound healing leads to scar formation. The phenomenon of scarless fetal healing has shown that healing can occur without exuberant inflammation. We propose to mimic this phenomenon in adult wounds by using agents that reduce inflammation. Nimesulide and Prostaglandin E2 were used to treat cutaneous wounds in rats. Assessment of histolo...

In skin wounds, the chemokine CXCR3 receptor appears to play a key role in coordinating the switch from regeneration of the ontogenically distinct mesenchymal and epithelial compartments toward maturation. However, because CXCR3 equivalently binds four different ELR-devoid CXC chemokines (ie, PF4/CXCL4, IP-10/CXCL10, MIG/CXCL9, and IP-9/CXCL11), we...

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To investigate the repair process following carbon dioxide laser injury to the upper airway mucosa (UAM) during the development of chronic subglottic stenosis (SGS). Animals were assigned to either sham control (cricothyroidotomy only) or injured (cricothyroidotomy and posterior subglottic laser) groups using various carbon dioxide laser exposures...

Background: Activation of the cyclooxygenase-2 (COX-2) pathway and production of prostaglandin E2 (PGE2), have been linked to dermal wound healing in fetal and adult tissue. Activation of this pathway has been previously linked to interleukin (IL)-1β expression. This study addresses the mechanism by which IL-1β regulates both production of and resp...

We find that the ELR-negative CXC chemokines, CXCL10 (IP-10) and CXCL11(IP-9), expressed during wound repair, with IP-9 being produced by redifferentiated keratinocyte. Immunohistochemical analysis for IP-9 on human full thickness wound tissues collected from day 5 confirmed that IP-9 is a wound response protein. We have shown in in vitro coculture...

Background: Prostaglandin E2 (PGE2) is an important inflammatory mediator, which has been shown to regulate fibroblast chemotaxis and extracellular matrix production through four G-coupled protein receptors (EP1, EP2, EP3, EP4). Previous studies have linked abnormal PGE2 signaling with the development of improper damage repair and tissue fibrosis i...

Scarless fetal wound healing in connective tissue is characterized by organized collagen deposition that leads to regeneration and apparently normal tissue structure and function. In contrast, adult wound healing is characterized by the deposition of unorganized collagen that leads to scar formation and a loss of functionally relevant structural or...

The development of personalized medicine is a primary objective of the medical community and increasingly also of funding and registration agencies. Modeling is generally perceived as a key enabling tool to target this goal. Agent-Based Models (ABMs) have previously been used to simulate inflammation at various scales up to the whole-organism level...

Fetal dermal fibroblasts participate in a dramatically different wound healing process compared to their adult counterparts, and it is thought that their intrinsic phenotype contributes to the unique properties of fetal repair. In particular, fibroblast migratory and contractile properties have been shown to be important in the development or lack...

Despite the fact that vocal folds are subjected to extensive mechanical forces, the role of mechanical strain in vocal fold wound healing has been overlooked. Recent studies on other tissues have demonstrated that low physiological levels of mechanical forces are beneficial to injured tissues, reduce inflammation, and induce synthesis of matrix-ass...

To delineate age-dependent and tissue-specific molecular activities of the variant-inclusion fibronectin transcripts in fetal and postnatal skin and airway mucosal wounds during early events of the wound healing process. Fibronectin is involved in multiple steps of the wound healing process. The functional complexity of fibronectin is carried throu...

Replacement of wounded skin requires the initially florid cellular response to abate and even regress as the dermal layer returns to a relatively paucicellular state. The signals that direct this "stop and return" process have yet to be deciphered. CXCR3 chemokine receptor and its ligand CXCL11/IP-9/I-TAC are expressed by basal keratinocytes and CX...

In contrast to fetal wound healing, dermal adult wound healing results in imperfect repair and scar formation. Fibroblasts are responsible for the contraction and remodeling of the wound matrix, which is influenced by inflammatory mediators including prostaglandin E2 (PGE2). This study addresses the mechanism by which PGE2 regulates contraction of...

To determine whether (1) inflammatory mediators IL-1beta (interleukin 1beta) and prostaglandin E2 (PGE2) in mucosal secretions correlate with subglottic mucosal injury; and (2) mucosal fibroblasts contribute to PGE2 production during mucosal healing. The subglottic mucosa in rabbits was wounded by means of varied carbon dioxide laser power and dura...

To conduct an endoscopic and histologic analysis of the subglottic effects of various carbon dioxide laser-induced injuries in the rabbit model. Animals were assigned to either a control (cricothyroidotomy only) group or 4 (cricothyroidotomy and posterior subglottic laser) groups that were injured using varying systematically controlled carbon diox...

To evaluate the effects of the ciprofloxacin-dexamethasone (CDX) combination ototopical treatment after myringotomy on tympanic membrane (TM) healing in ears with eustachian tube obstruction (ETO) and unobstructed ears. Prospective, randomized, masked, controlled. ETO was created in the left ear of 30 rats to induce a model of otitis media with eff...

The mechanisms that control Streptococcus pneumoniae's ability to colonize the nasopharynx or to invade the middle ear and cause acute otitis media are not understood. Focused study of these mechanisms requires efficient methods for the extraction of microbial RNA from minute clinical samples. Several lysis/extraction methods were tested and compar...

Keloid formation has been linked to aberrant fibroblast activity, exacerbated by growth factors and inflammatory mediators. Prostaglandin E2 (PGE2), synthesized from arachidonic acid by cyclooxygenases (COX) and synthases (PGES), acts as both an inflammatory mediator and fibroblast modulator. Although PGE2 has known antifibrotic effects in the lowe...

A study was conducted to determine whether negative air pressure, relative to atmospheric pressure, induces middle ear mucosal epithelial cells to release inflammatory mediators. A human middle ear epithelial cell line was used to set up cultures in transwell plates. Cells were seeded onto inserts forming the upper chambers and grown to confluence,...

To investigate hepatocyte growth factor (HGF) primed fibroblasts and decorin application on skin and vocal fold fibroblasts in vitro and in vivo in rabbit vocal fold scar model. Vocal fold and skin fibroblasts underwent five in vitro treatment conditions: control, epidermal growth factor, HGF, both decorin and HGF, and decorin alone. Hyaluronic aci...

The basic science of wound healing is largely omitted from the curriculum of many voice clinicians. This fact is relatively disheartening as most therapeutic manipulation in the realm of laryngology and voice disorders deals with injured tissue. Therefore, the selection of therapeutic tasks for persons with vocal injury should ideally be informed b...

Cyclooxygenase-2 is up-regulated shortly after dermal injury and it has been shown to have important activity during the repair process. Its main product in the skin, prostaglandin E2 (PGE2), modulates both inflammatory and fibrotic processes during wound healing and partially dictates the overall outcome of wound healing. PGE2 signaling has been s...

Keloid scars after skin trauma are a significant clinical problem, especially in black populations, in which the incidence of keloids has been estimated at 4-16%. Keloids are abnormal dermal proliferative scars secondary to dysregulated wound healing. Despite several biochemical studies on the role of extracellular matrix proteins and growth factor...

Fibronectin (FN) is a multi-functional, adhesion protein and involved in multi-steps of the wound healing process. Strong evidence suggests that FN protein diversity is controlled by alternative RNA splicing; a coordinated transcription and RNA processing that is development-, age-, and tissue/cell type-regulated. We previously demonstrated that fe...

Because subglottic stenosis (SGS) represents one of the most challenging pathologies confronting the pediatric otolaryngologist, our laboratory is investigating the role fibroblasts play in mucosal scar formation in the course of SGS development. Our objective is to establish cell transplantation into the subglottic mucosal wound bed as a viable to...

To define the gene expression patterns during the early phases of a bacterial middle ear infection in the rat model. Using cDNA gene array technology, we profiled the mRNA expression of 1176 genes in a rat model of acute otitis media. We identified changes in gene expression two-fold or greater 12 and 48 h after bilateral ME inoculation with either...

An increased awareness of bacterial biofilms and their formation has led to a better understanding of bacterial infections that occur in the middle ear. Perhaps the best studied pathogen for its propensity toward biofilm formation is Pseudomonas aeruginosa, also the primary pathogen in chronic suppurative otitis media (CSOM). The aim of this study...

This study seeks to determine the ability of enzyme-linked immunosorbent assays (ELISAs) of vocal fold secretions to detect and describe the acute tissue response to injury in a rabbit vocal fold model. Vocal fold secretions were collected before the induction of a unilateral surgical injury to the vocal fold and at 6 timepoints after injury (1, 5,...

To build on work in laryngology and oral biology that suggests utility in the assay of secretions collected from wound sites as a predictive instrument to determine which infants will likely develop subglottic stenosis following endotracheal intubation and to document and describe the wound-healing process. Prospective, randomized design. Laser-ind...

Wound healing is a complex process involving close cooperation between multiple cell types. During wound healing, fibroblasts are primarily responsible for synthesis of the replacement extracellular matrix. Fibroblast therapy is under investigation in this and other laboratories for its potential use to modulate the final outcome of the wound-heali...

Several authors have eloquently described the characteristics of vocal fold scar, a long-term consequence of vocal fold injury. However, events in the acute stage of mucosal injury, which lead up to fibrosis, have been largely overlooked. The current study describes acute events with regard to mucosal re-formation in a rabbit model. Vocal fold inju...

Objectives/hypothesis: Acute otitis media, often caused by infection with Streptococcus pneumoniae, is characterized by inflammation of the middle ear mucosa. A prominent feature of the host response to bacterial infection of the middle ear mucosa is an influx of inflammatory cells that contributes to the local pool of inflammatory mediators by re...

Background: Wound healing is a complex process involving multiple cell types, extracellular matrix components and soluble mediators. Prostaglandin E2 is an important component of the inflammatory response to injury. PGE2 can regulate the fibroblast response to injury via the EP receptor family. Here, we examine PGE2 regulation of fibroblast migrati...

Keloids, which overgrow the boundaries of the original injury, represent aberrations in the fundamental process of wound healing that include over-abundant cell in-migration, cell proliferation, and inflammation, as well as increased extracellular matrix synthesis and defective remodeling. To understand the key events that result in the formation o...

This study seeks to determine the ability of enzyme-linked immunosorbent assays of vocal fold secretions to detect and describe the inflammatory response in the vocal folds. Vocal fold and palatal secretions were collected during operation from patients with a range of vocal fold disorders and from control patients. The secretions were subjected to...

Objectives: To utilize an established animal model to test the ability of topical sirolimus, a macrolide immunosupressant, to prevent or reduce subglottic stenosis.Methods: Pasturella-free New Zealand white rabbits were injured in the subglottic mucosa by a cricoid split procedure and laser. Each of the rabbits in 3 groups received either saline, m...

The current study sought to determine whether shifts in key components of the inflammatory process could be detected from laryngeal secretions sampled before and after vocal loading. A healthy 44-year-old woman served as the subject. The vocal folds were swabbed to collect baseline secretions. Ten and 20 minutes after nearly constant loud phonation...

The purpose of the present study was to compare the effect of 24 h of exposure to 7% O2 (normal middle ear physiological conditions) vs. 21% O2 (found in the middle ear after ventilation tube placement) on transepithelial Na+ absorption and Cl- secretion in cultured gerbil middle ear epithelial cell monolayers. Although no difference in apical Na+...

Temporally controlled expression of genes in transgenic mice has advanced our understanding of many physiological processes. One of the more common modes of acutely altering gene levels involves the doxycycline-regulated "tet-on/tet-off" systems. There has been concern that the administration of doxycycline in itself might compromise many aspects o...

Recently, we reported that gene transcripts encoding 3 Na+ transport proteins (pump, channel and exchanger) in the middle ear mucosa (MEM) were simultaneously suppressed at 12 and 48 h after Streptococcus pneumoniae (SP) challenge of rat middle ears. From cDNA microarray screening of those specimens, several gene clusters, including Nos2 and the tr...

To determine the effect of injected fibroblasts on full-thickness cutaneous wounds and to distinguish between the properties of fetal vs adult fibroblasts. Full-thickness cutaneous wounds were created by incision in the skin of adult New Zealand white rabbits and treated with fluorescently labeled autogenic, allogenic, and xenogenic fetal and adult...

Cytokine expression was studied in a rat model of otitis media with effusion. The left eustachian tube was obstructed (eustachian tube obstruction [ETO]) in 84 rats. Forty-two ears were challenged with, and those rats were treated from day 2 to day 7 with ampicillin. Twelve rats (6 per group) were killed on days 1, 2, 7, 21, 35, 56, and 112; mucosa...

Until recently, it was not feasible to conduct genome-wide screening for gene transcript variations that play key roles in the pathogenesis of otitis media. In this study microarray technology was used to profile differential gene expression patterns from rat middle ear mucosa at 12 and 48 h after Streptococcus pneumoniae challenge. Real-time polym...

To describe the clinical and histopathologic progression of a rat model of otitis media with effusion caused by eustachian tube obstruction (ETO) with and without Streptococcus pneumoniae infection. In 164 rats, the left, bony eustachian tube was approached via a ventral incision and obstructed with dental material. Then 108 rats were infected via...

Ten drugs were screened for their ability to decrease inflammatory mediator (IL-6, inducible nitric oxide synthetase [iNOS], IL-1beta and monocyte chemotactic protein [MCP-1]) expression in a rat model of acute otitis media caused by Streptococcus pneumoniae. Six adult rats were randomly assigned to each of 12 groups corresponding to uninfected con...

Debridement of necrotic eschar from wounds can be accomplished with the application of proteolytic enzyme formulations. However, a clear understanding of the biochemical activities of the enzymatic agents is essential for achieving effective wound debridemenf. This report describes the in-vitro evaluation of the active ingredients of several commer...

Scar formation and subglottic stenosis often cause health problems in surgical otolaryngology. However, fetal wounds demonstrate scarless healing. The underlying mechanism remains poorly understood. We isolated differentially expressed genes by comparison between nonwounded with wounded skin of fetal and adult rabbits. Skin incisional wounds were m...

Cell therapy and bioengineering hold great promise as therapeutic approaches using cells and cell-derived factors to treat various pathologic or trauma-induced states. One possible application is the transplantation of cells into wounded tissue to help regulate tissue repair. Cells engineered for optimal wound healing may help to minimize scarring...

Scars form as wounds heal in adult organisms. In addition to disrupting cosmetic appearance, scar tissue can cause significant morbidity, and even death if it blocks vital organ function. Previous work has established that fetal wounds, especially in early to midgestation, can heal without scarring. Because such inherent physiological mechanisms ul...

To investigate the safety and efficacy of a topical combination of tobramycin and dexamethasone in a primate model of chronic suppurative otitis media (CSOM) and to explore the contribution of the added topical steroid for the treatment of CSOM. Blinded, randomized, placebo-controlled trial. Sixty juvenile cynomolgus monkeys randomized into the fol...

Cell therapy is a widely applicable therapeutic approach using cells and cell elements, frequently from fetal or young animals, for their beneficial effects. This study evaluated the host response to and tolerance of transplanted fetal skin fibroblasts. Cultured fibroblasts from adult rabbit skin (autogenic and allogenic), 21-day fetal rabbit skin...