0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Clinical Sciences |

Correlations of Long-term Matrix Metalloproteinase Localization in Human Corneas After Successful Laser-Assisted In Situ Keratomileusis With Minor Complications at the Flap Margin FREE

Pierre R. Fournié, MD; Gabriel M. Gordon, BS; Daniel G. Dawson, MD; Henry F. Edelhauser, PhD; M. Elizabeth Fini, PhD
[+] Author Affiliations

Author Affiliations: Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida (Drs Fournié, Dawson, and Fini and Mr Gordon); Institut national de la santé et de la recherche médicale (INSERM), U563, Université Toulouse III Paul Sabatier, and Service d’Ophtalmologie, Hôpital Purpan, CHU Toulouse, Toulouse, France (Dr Fournié); and Emory Eye Center, Emory University, Atlanta, Georgia (Drs Dawson and Edelhauser).


Arch Ophthalmol. 2008;126(2):162-170. doi:10.1001/archophthalmol.2007.64.
Text Size: A A A
Published online

Objective  To determine whether matrix metalloproteinases (MMPs) are present long-term in human corneas after successful laser-assisted in situ keratomileusis (LASIK).

Methods  Eighteen postmortem corneas from 10 patients with postoperative intervals of 2 to 8 years after LASIK surgery and 4 normal control corneas from 2 patients were collected from US eye banks and processed for histologic analysis and immunolocalization with antibodies to MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, and MMP-14.

Results  Matrix metalloproteinase 7 was present in the epithelium of all corneas. Other MMPs were localized to the wound margin in some post-LASIK corneas. Matrix metalloproteinase 9 was detected around epithelial cells trapped in the lamellar scar in 5 of 6 corneas with epithelial ingrowth. Various MMPs were detected in fibrotic tissue at the wound margin in 2 of 2 corneas with flap retraction.

Conclusions  The presence of MMPs in post-LASIK corneas correlates with an ongoing wound healing process associated with minor post-LASIK complications. Matrix metalloproteinases might contribute to instances of ongoing flap instability, and if so, judicious use of MMP inhibitors could provide benefit.

Figures in this Article

Laser-assisted in situ keratomileusis (LASIK) has certain advantages relative to other refractive surgical procedures, including little or no significant central haze, less myopic regression, faster visual recovery, and less postoperative discomfort; thus, it is currently the most frequently performed refractive surgical procedure in the world.1 In LASIK procedures, damage to the epithelial basement membrane occurs only at the flap margins, providing only minimal opportunity for direct epithelial-stromal cell interactions required to stimulate the fibrotic repair response responsible for haze.24 Recent studies of human postmortem corneas reveal that central and paracentral LASIK wounds heal by producing a hypocellular primitive stromal scar5,6 that has a very weak cohesive tensile strength7 and displays no evidence of remodeling over time for up to 6.5 years postsurgery. It is only the region localized around the flap margin of the LASIK cornea adjacent to the surface epithelium that heals by fibrosis. This healing produces a hypercellular fibrotic stromal scar that reaches maximal tensile strength by approximately 3.5 years postsurgery, implying a much longer healing time than previously thought.57

Matrix metalloproteinases (MMPs) are a family of enzymes that constitute the principal mediators of tissue remodeling in physiology and pathology.812 As a family, they are capable of dismantling virtually any extracellular matrix structure and they also act on a large number of other substrates, including cytokines and cell adhesion molecules.13,14 Matrix metalloproteinases are typically secreted in a latent form that must undergo an internal cleavage to be activated. The MMP family currently includes more than 25 members that can be divided into 5 subfamilies based on substrate preference: collagenases (MMP-1, MMP-8, and MMP-13), stromelysins (MMP-3 and MMP-10) and matrilysins (MMP-7 and MMP-26), gelatinases (MMP-2 and MMP-9), membrane-type MMPs (MMP-14 to MMP-17 and MMP-24), and others. Most MMPs occur naturally only in very low levels in normal tissue. In fact, their expression is tightly regulated, induced only when needed, so as to avoid uncontrolled and excessive tissue destruction.15 Matrix metalloproteinase expression is transcriptionally up-regulated in resident tissue cells during wound healing, regeneration, and remodeling; MMPs are also brought in by invading leukocytes, which both synthesize and store MMPs.2,1518

The cornea has been an important experimental model for defining mechanisms of MMP expression and role in normal and pathologic repair processes, including epithelial regeneration and failure to heal, fibrotic repair and scar remodeling, infection, and angiogenesis.2,16,1937 These studies have revealed that specific MMPs appear in specific locations in the repairing cornea correlated with events occurring on the cellular and tissue level. For example, MMP-9 is produced in the corneal epithelium regenerating across the intact basement membrane after abrasion injury and then disappears once regeneration is complete.19 However, in situations involving chronic epithelial defects, MMP-9 levels remain elevated, causally contributing to failure to heal.21,22 Similarly, a number of different MMPs are produced by the fibrotic repair tissue deposited in response to keratectomies that penetrate through the epithelium and into the stroma.20 In this case, MMP expression continues long-term, at least 1.5 years, as documented in a rabbit penetrating keratectomy model, correlated with the lengthy process of repair tissue remodeling. Some of the reports evaluating MMP expression in more specific models of photorefractive keratectomy and LASIK23,24 and corneal button specimens obtained after penetrating keratoplasty for photorefractive keratectomy or post-LASIK complications3840 have supported similar conclusions in the short-term, but the long-term studies have not been done.

The purpose of the present study was to determine whether MMPs continue to be expressed long-term in human corneas after reportedly uncomplicated successful LASIK. All corneas were obtained postmortem from US corneal eye bank donors at varying intervals after LASIK surgery. We also investigated factors, including patient age, postoperative interval, and histopathologic findings, that could affect MMP expression.

SOURCE OF THE CORNEAS

After approval by the Emory University institutional review board, 18 postmortem corneoscleral buttons from 10 corneal eye bank donors with a history of LASIK surgery were obtained from various eye banks in North America. A number was assigned to each cornea according to the order of inclusion. The specimens were received in Optisol-GS solution (Bausch & Lomb Surgical, Irvine, California) within 6 days of death (mean [SD] time of preservation, 3.51 [1.4] days). Review of preoperative, intraoperative, and postoperative clinical records, when available, was performed. Four postmortem normal corneas stored in Optisol-GS (mean [SD] time of preservation, 2.95 [0.35] days) from 2 patients were obtained from the Georgia Eye Bank (Atlanta) and the Lions Eye Bank (Miami) as controls.

CORNEAL PROCESSING

The corneoscleral buttons were oriented with the hinge superiorly and then trisected. The central portion was immediately snap-frozen in liquid nitrogen, embedded in optimal cutting temperature compound (Tissue-Tek-II; Miles Inc, Elkhart, Indiana), and stored at −70°C until sectioned. Sections (8 μm) were cut in a cryostat microtome (Leica 1850 cryostat; Leica, Deerfield, Illinois) and mounted on adhesive-coated glass slides for conventional and immunofluorescent histologic processing. Normal control corneas were sectioned centrally and processed identically as LASIK corneas.

HISTOLOGIC EXAMINATION

The sections were fixed and stained with hematoxylin-eosin according to standard procedures. Histopathologic findings from light microscopic examination of the peripheral lamellar wound at the flap margin and central lamellar wound, flap thickness (taken from a representative area with the fewest artifacts and containing all 3 distinct types of epithelial cells: basal, wing, and superficial epithelial cells), and residual stromal bed thickness measurements using a Zeiss Axiovert 200M inverted microscope (Carl Zeiss Meditec, Jena, Germany) coupled to a Zeiss AxioCam MRc5 camera (Carl Zeiss Meditec) were recorded.

ANTIBODIES

Polyclonal antibodies to MMPs were purchased from Triple Point Biologics (Forest Grove, Oregon): rabbit antibodies to interstitial collagenase (RHMMP1), gelatinase A (RHMMP2), stromelysin 1 (RP2MMP3), MMP-7 (RP2MMP7), neutrophil collagenase (RP1MMP8), gelatinase B (RP3MMP9), stromelysin 2 (RP2MMP10), and membrane-type MMP-1 (RP2MMP14). Rabbit monoclonal anti-CD11b (Mac-1) (clone M1/70.15) was obtained from Cedarlane Laboratories (Burlington, North Carolina). CD11b (Mac-1) was used as a marker for leukocytes, including macrophages and granulocytes. Rabbit polyclonal antilaminin (L9393) and mouse monoclonal α-smooth muscle actin (α-SMA) (clone 1A4) were purchased from Sigma-Aldrich (St Louis, Missouri). Rabbit IgG and mouse IgG (Chemicon, Temecula, California) were purchased as negative controls. Secondary antibodies used were Alexa Fluor 488 conjugated goat antimouse IgG (A-11001) and donkey antirabbit IgG (A-21206) from Invitrogen Molecular Probes (Carlsbad, California).

INDIRECT IMMUNOLOCALIZATION

Slides to be stained were air-dried for 20 minutes at room temperature and then fixed in 100% cold acetone (−20°C) for 20 minutes. They were washed with phosphate-buffered saline (PBS) 3 times for 5 minutes each, followed by a 1-hour incubation in a humidified level chamber in 10% normal donkey (D9663, Sigma-Aldrich) or goat (G9023, Sigma-Aldrich) serain PBS to block nonspecific staining. Primary antibodies were used in a dilution of 1:100 and incubated at 4°C overnight. After 3 additional washes with PBS for 5 minutes each, the Alexa Fluor 488 conjugated secondary antibody was applied for 1 hour. Samples were mounted with the Vectashield mounting medium with 4',6-diamidino-2-phenylindole (Vector Laboratories, Burlingame, California) for nuclear counterstaining. Negative control sections were processed identically but incubated with strain-specific IgG as primary antibodies. Samples were examined using a Zeiss Axiovert 200M inverted fluorescence microscope and images were captured using a Zeiss AxioCam MRc5 camera attached to the microscope. Camera and microscope settings were controlled by Axiovision software version 4.1 (Carl Zeiss Meditec). To evaluate the effect of LASIK, 4 regions were evaluated: (1) the LASIK flap wound margin, (2) the corneal stroma in the LASIK flap, (3) the paracentral and central lamellar wound regions, and (4) the residual stromal bed. Normal control corneas were evaluated in the central, paracentral, and peripheral regions. The LASIK flap wound margin was also examined using a Leica TCS SP2 confocal microscope (Leica Microsystems, Bannockburn, Illinois) with a total magnification of × 400.

DATA ANALYSIS

The slides were evaluated for staining intensity, cellular localization of staining, and the presence of any distinctive staining patterns. Immunoreactivity intensity was evaluated using a semiquantitative scale with the negative control as baseline (− = none or same as background, + = weak [trace or slightly perceptible above background], ++ = moderate, and +++ = strong). Reliability was assessed by having 2 evaluators independently rate the staining intensities at different times. The average of the 2 observers' scores was used. Concordance among the observers was high.

CLINICAL FINDINGS

A complete history of the LASIK surgeries could not be obtained for the majority of the 18 specimens. Clinical data that were available for every specimen included patient age, cause of death, a history of uncomplicated LASIK, and the postoperative interval after LASIK (Table 1). Patient 10 underwent LASIK with 2 enhancements by flap relifting 6 and 12 months after initial surgery and a third enhancement 4 years after the initial surgery by recutting a flap (Figure 1E). The 10 patients ranged in age from 34 to 62 years (mean [SD], 50.30 [7.15] years). The postoperative interval after LASIK ranged from 2 to 8 years.

Place holder to copy figure label and caption
Figure 1.

Light microscopy of laser-assisted in situ keratomileusis (LASIK) flaps (hematoxylin-eosin, original magnification × 200). Histopathologic findings of the peripheral LASIK wound margin regions (arrowheads) display varying healing modalities. A, “Normal healing” with good alignment of Bowman’s layer ends (patient 4R). B, Epithelial hyperplasia with depressed Bowman’s layer end (patient 3L). C, Epithelial ingrowth (patient 1). D, Bowman’s layer end curled inward with a flap retraction (patient 5R). E, Double-cut LASIK with the second cut deeper and wider (patient 10).

Graphic Jump Location
HISTOLOGIC FINDINGS

Hematoxylin-eosin–stained light microscopy evaluations revealed a lamellar interface scar that was relatively easy to find (Figure 1) in all the specimens. The mean (SD) central thickness of the LASIK flap was 130 (21) μm. The mean (SD) residual stromal bed thickness was 353 (39) μm (Table 2). At the LASIK flap wound margin, some corneas had variable amounts of epithelial ingrowth into the lamellar wound (Figure 1C), microscopic foci or islands of epithelial cells actually in the scar, and variability in the alignment of the cut end of Bowman’s layer at the wound margin (eg, good alignment with a small gap at the break [Figure 1C], depressed or elevated ends [Figure 1B], and ends curled inward with various flap retraction and stromal defects [Figure 1D]). Epithelial ingrowth into the flap margin was observed in 6 of the 18 corneas (33.3%) examined using serial sections. Variable amounts of epithelial hyperplasia (Figure 1B) were commonly present at the wound margin, filling the gaps in Bowman’s layer. The histologic findings in the wound margin are summarized in Table 2. Corneas were grouped according to their main histopathologic finding at the wound margin.

IMMUNOSTAINING FINDINGS

Staining of normal control corneas was the same in the central, paracentral, and peripheral regions: only MMP-7 was detectable in 2 of the 4 normal control corneas with at least ++ staining intensity, localized in the epithelium (Table 3). A number of different MMP proteins were immunodetected in the wound margin of LASIK corneas. Semiquantitative staining intensity results in the wound margin are summarized in Table 3. No staining was observed at the paracentral or central scar regions. All other regions in the corneal stroma were unstained. The negative control serving as reference for immunofluorescence intensity evaluation is shown for each Figure. Matrix metalloproteinase 9 immunostaining with a level of at least ++ was observed in 5 (patients 1, 7L, 9R, 9L, and 10) of the 6 corneas with epithelial ingrowth. Immunoreactive MMP-9 protein was detected around epithelial cells trapped in the lamellar scar (Figure 2C and Figure 3B). The most MMPs within the defect area at the wound margin were detected in corneas from the 2 patients (patients 2L and 5R) (Figure 4) with the ends of Bowman’s layer curled inward with flap retraction. This area was also positive for CD11b (Mac-1), a marker for granulocytes or macrophages, in the corneas of these 2 patients (Figures 4E). In 3 corneas, α-SMA, a marker for myofibroblast differentiation, was detected within the margin defect of the right cornea of patient 5 (Figure 4I) and of the left cornea of patient 2 and in keratocytes between both flap cuts of patient 10 (Figure 3E-F).

Place holder to copy figure label and caption
Figure 2.

Immunofluorescence of a cornea after laser-assisted in situ keratomileusis complicated by an epithelial ingrowth (patient 1). A-C, Positive staining for matrix metalloproteinase 7 (B) and matrix metalloproteinase 9 (C) around epithelial cells trapped in the lamellar scar compared with the negative control (rabbit IgG) (A) (A and B, original magnification × 400; C, original magnification × 630). D, Discontinuous epithelial basement membrane laminin was observed (arrow) (original magnification × 630).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Immunofluorescence of double-cut laser-assisted in situ keratomileusis in patient 10. A, Negative control (rabbit IgG) (original magnification × 400). B, Positive staining for matrix metalloproteinase 9 was observed around some epithelial cells trapped within the peripheral scar of the first cut (original magnification × 630). C, Irregular epithelial basement membrane laminin was observed (original magnification × 400). D, Negative control (mouse IgG). Arrow points to the peripheral edge of the second cut (original magnification × 400). E and F, Cells positive for α–smooth muscle actin (arrowheads) were observed in the stroma (E, original magnification × 400; F, original magnification × 1000).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Immunofluorescence of the laser-assisted in situ keratomileusis flap margin of patient 5R with flap retraction. A-E, Positive staining for matrix metalloproteinase (MMP) 3 (B), MMP-7 (C), MMP-8 (D), and Mac-1 (CD11b) (arrows) (E) was observed within the margin defect compared with the negative control (rabbit IgG) (A). F and G, No MMP-9 staining (F) or continuous epithelial basement membrane laminin (G) were observed. I and H, Note the presence of α–smooth muscle actin (I) within the defect compared with the negative control (mouse IgG) (H) (A-I, original magnification × 400).

Graphic Jump Location
Table Graphic Jump LocationTable 3. Immunostaining Findings in the LASIK Wound Margin (Groups 1-4) and in the Control Group

Matrix metalloproteinases are expressed by resident tissue cells in response to injury and remodeling stimuli and are also produced by inflammatory cell types that invade the tissue during remodeling events. Collagenase is the prototype member of the MMP family, its activity first demonstrated in the involuting tadpole tail.41,42 When applied shortly thereafter to the cornea, this discovery gave the first insight into the enzymatic basis of corneal ulceration.4345 Work in the 1970s characterized corneal collagenase in normal and pathologic repair.36,46 With the molecular cloning of collagenase, and expansion of the MMP family, and development of molecular and antibody probes,10 investigation in the cornea was renewed and expanded into new territory.37,47 Much subsequent work has defined complex roles for MMPs in normal and pathologic corneal repair and remodeling processes.2,16 The results of studies using transgenic mice (knockouts or overexpression) emphasize the high functional redundancy of MMPs.48 The ablation of a particular MMP can lead to higher expression levels of other MMPs, presumably to compensate for the loss. In view of this fact, it is thought that the multiplicity of MMP forms is an indicator of the extreme importance of these enzymes for the maintenance and repair of tissues.8

This study of adult human corneas that underwent uneventful LASIK 2 to 8 years before evaluation revealed that MMPs, when present, are localized exclusively to the flap margin. Matrix metalloproteinase presence was correlated with specific histopathologic findings identified at the wound margin. There was no observable correlation between patient age or postoperative interval with the severity or type of MMP activity in corneas that underwent LASIK.

Of the 33% (n = 6) of corneas with epithelial ingrowth observed in the current series, 83% (n = 5) had at least ++ immunostaining for MMP-9, which was positively correlated with basement membrane interruption or irregularities visualized via laminin staining. This is consistent with the capacity for MMP-9 to cleave epithelial basement membrane components, such as collagen types IV and VII and laminin.8,11 New basement membrane components such as laminin and type IV collagen are deposited underneath migrating corneal epithelial cells19 and around corneal epithelial cells implanted into the stroma.49 A causal relationship between overexpression of MMP-9 in the corneal epithelium and basement membrane dissolution/failure to heal has been demonstrated in experimental models.21,22 In these studies, the corneal epithelium gave the appearance of an invading front, dissolving the basement membrane and subsequently penetrating the underlying stroma in its path. Matrix metalloproteinase 9 associated with a disrupted basement membrane around ingrowing epithelium suggests a similar chronic, ongoing remodeling and invasion process and might help explain the previous findings identifying the weakest wound margin scars as those with epithelial ingrowth.7

Matrix metalloproteinase 7 immunostaining is observed around trapped epithelial cells with the same intensity as in control corneas. Matrix metalloproteinase 7 was immunolocalized in previous studies to the epithelial layers of unwounded and wounded corneas in rat.26 In this study, MMP-7 was also found in the epithelium of corneas from groups 1 and 3 but not specifically at the stromal wound margin. This is in comparison with corneas of groups 2 and 4 where MMP-7 was localized under the epithelial surface: around trapped epithelial cells in epithelial ingrowth (group 2) and in the overlying wound stroma in group 4. We thus did not mention MMP-7 in the wound margin of groups 1 and 3 in Table 3. Unlike most MMPs, MMP-7 (matrilysin) is constitutively present in uninjured epithelia, including in the intestine,50 airways,51 and cornea.26 In the small intestine, MMP-7 has been shown to function in host defense by activating the latent form of defensins, a family of antimicrobial peptides that are also found in the cornea.47 In models of airway51 and corneal injury,26 MMP-7 expression is up-regulated in migrating epithelial cells, and the MMP-7 activity is required for repair of airway wounds. These observations indicate that matrilysin serves key functions in both epithelial defense and repair.

Various MMPs were detected at flap margins with flap retraction (patients 2L and 5R). In both cases, Mac-1 (CD-11b), used as a marker for macrophages and granulocytes, was colocalized, suggesting a chronic inflammatory process. This can explain the expression of various MMPs, particularly the presence of the neutrophil collagenase (MMP-8), which is synthesized specifically by polymorphonuclear neutrophils.8 Also, α-SMA–positive cells, a marker of the “myofibroblast,” were observed in the stroma layer near the edge of the flap in these 2 corneas. A similar α-SMA expression pattern was reported in human corneas up to 6 years after LASIK surgery.6 Myofibroblasts expressing α-SMA are associated with a highly fibrotic wound phenotype characterized by a significant deposition of repair-type extracellular matrix, significant hypercellularity, and extensive repair tissue contraction. In the cornea, myofibroblasts are also associated with repair tissue opacity.52 When repair tissue deposition reaches its peak, the fibrotic phenotype and myofibroblast markers first begin to resolve. In a fully healed wound, there are few if any myofibroblasts.4,52 Long-term expression in some post-LASIK corneas emphasizes the chronic, ongoing nature of the fibrotic wound healing process.

Our study represents the first investigation, to our knowledge, of MMP expression in a series of clinically uneventful human LASIK refractive procedures. Reports of MMP expression following complicated LASIK procedures are also rare and consist mainly of case reports. Maguen et al38 studied 2 corneas that underwent a complicated LASIK procedure. They reported anterior stromal expression of MMP-1, MMP-2, and MMP-7 in the epithelium in a torn flap and an ectatic cornea. They did not report presence of MMPs following a single uneventful LASIK procedure performed several years earlier. This is consistent with our study as we found that MMPs are present only in corneas with specific histopathologic findings.

In the absence of keratoconus or forme fruste keratoconus, progressive post-LASIK keratectasia might be the result of biomechanical instability or a chronic disease process with progressive enzymatic degradation.53 An imbalance in proteolytic breakdown and repair could lead to a progressive stromal melting. The spatial localization of MMPs at the wound margin seen in our study does not support a role in ectasia, a process that primarily involves central changes in the post-LASIK cornea. On the other hand, epithelial ingrowth and cicatricial changes at the flap edges could relate to reduced resistance of some LASIK corneas to shearing trauma, resulting in late flap displacements.

In conclusion, to our knowledge, this is the first study to report that MMP proteins can be detected in some post-LASIK corneas even after many years. The presence of MMPs correlates with an ongoing, highly localized wound healing process at the flap margin, associated with minor post-LASIK complications. We cannot say with certainty whether epithelial ingrowth, flap retraction, or the ongoing repair process this signifies is the cause or the consequence of MMP presence. However, we propose that minor defects in the surgically created flap might interfere with perfect alignment with the underlying cornea following surgery. This would predispose to slippage, creating space for epithelial ingrowth and a chronic requirement for fibrotic repair. Like other chronic repair processes, MMP expression might become excessive because of ever-amplifying feedback loops, and this could gradually evolve into a contributing factor in failure to heal. In such situations, judicious and timely use of appropriate MMP inhibitors might provide some benefit, inhibiting epithelial ingrowth and enabling fibrotic repair tissue to accumulate sufficiently to “tack” the flap in place.

Correspondence: M. Elizabeth Fini, PhD, McKnight Vision Research Center, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, 1638 NW 10th Ave, Miami, FL 33136 (efini@med.miami.edu).

Submitted for Publication: February 25, 2007; final revision received June 3, 2007; accepted June 10, 2007.

Author Contributions: Dr Fournié and Mr Gordon are co–first authors and contributed equally.

Financial Disclosure: None reported.

Funding/Support: This work was supported by National Eye Institute grants R01-EY012651 (Dr Fini), P30-EY014801 (Dr Fini), and R01-EY00933 (Dr Edelhauser), unrestricted grants from Research to Prevent Blindness (to University of Miami and Emory University), a Senior Scientific Investigator Award (Dr Fini), and the Walter G. Ross Foundation (Dr Fini).

Sandoval  HPde Castro  LEVroman  DTSolomon  KD Refractive Surgery Survey 2004. J Cataract Refract Surg 2005;31 (1) 221- 233
PubMed Link to Article
Fini  MEStramer  BM How the cornea heals: cornea-specific repair mechanisms affecting surgical outcomes. Cornea 2005;24 (8) ((suppl)) S2- S11
PubMed Link to Article
Wilson  SEMohan  RRHutcheon  AE  et al.  Effect of ectopic epithelial tissue within the stroma on keratocyte apoptosis, mitosis, and myofibroblast transformation. Exp Eye Res 2003;76 (2) 193- 201
PubMed Link to Article
Stramer  BMZieske  JDJung  JCAustin  JSFini  ME Molecular mechanisms controlling the fibrotic repair phenotype in cornea: implications for surgical outcomes. Invest Ophthalmol Vis Sci 2003;44 (10) 4237- 4246
PubMed Link to Article
Dawson  DGHolley  GPGeroski  DHWaring  GO  IIIGrossniklaus  HEEdelhauser  HF Ex vivo confocal microscopy of human LASIK corneas with histologic and ultrastructural correlation. Ophthalmology 2005;112 (4) 634- 644
PubMed Link to Article
Dawson  DGKramer  TRGrossniklaus  HEWaring  GO  IIIEdelhauser  HF Histologic, ultrastructural, and immunofluorescent evaluation of human laser-assisted in situ keratomileusis corneal wounds. Arch Ophthalmol 2005;123 (6) 741- 756
PubMed Link to Article
Schmack  IDawson  DGMcCarey  BEWaring  GO  IIIGrossniklaus  HEEdelhauser  HF Cohesive tensile strength of human LASIK wounds with histologic, ultrastructural, and clinical correlations. J Refract Surg 2005;21 (5) 433- 445
PubMed
Woessner  JF  Jr The matrix metalloproteinase family. Parks  WCMecham  RPMatrix Metalloproteinase. San Diego, CA Academic Press1998;300- 356
Page-McCaw  AEwald  AJWerb  Z Matrix metalloproteinases and the regulation of tissue remodeling. Nat Rev Mol Cell Biol 2007;8 (3) 221- 233
PubMed Link to Article
Brinckerhoff  CEMatrisian  LM Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 2002;3 (3) 207- 214
PubMed Link to Article
Nagase  HVisse  RMurphy  G Structure and function of matrix metalloproteinases and TIMPs [published online ahead of print January 5, 2006]. Cardiovasc Res 2006;69 (3) 562- 573
PubMed Link to Article
Puente  XSSanchez  LMOverall  CMLopez-Otin  C Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 2003;4 (7) 544- 558
PubMed Link to Article
Somerville  RPOblander  SAApte  SS Matrix metalloproteinases: old dogs with new tricks [published online ahead of print May 29, 2003]. Genome Biol 2003;4 (6) 216
PubMed Link to Article
Overall  CMBlobel  CP In search of partners: linking extracellular proteases to substrates [published online ahead of print February 14, 2007]. Nat Rev Mol Cell Biol 2007;8 (3) 245- 257
PubMed Link to Article
Fini  MECook  JRMohan  RBrinckerhoff  CE Regulation of matrix metalloproteinase gene expression. Parks  WCMecham  RPMatrix Metalloproteinases. San Diego, CA Academic Press1998;300- 339
Sivak  JMFini  ME MMPs in the eye: emerging roles for matrix metalloproteinases in ocular physiology. Prog Retin Eye Res 2002;21 (1) 1- 14
PubMed Link to Article
Parks  WC Matrix metalloproteinases in repair. Wound Repair Regen 1999;7 (6) 423- 432
PubMed Link to Article
Lim  MGoldstein  MHTuli  SSchultz  GS Growth factor, cytokine and protease interactions during corneal wound healing. Ocul Surf 2003;1 (2) 53- 65
PubMed Link to Article
Matsubara  MGirard  MTKublin  CLCintron  CFini  ME Differential roles for two gelatinolytic enzymes of the matrix metalloproteinase family in the remodeling cornea. Dev Biol 1991;147 (2) 425- 439
PubMed Link to Article
Girard  MTMatsubara  MKublin  CTessier  MJCintron  CFini  ME Stromal fibroblasts synthesize collagenase and stromelysin during long-term tissue remodeling. J Cell Sci 1993;1041001- 1011
PubMed
Matsubara  MZieske  JDFini  ME Mechanism of basement membrane dissolution preceding corneal ulceration. Invest Ophthalmol Vis Sci 1991;32 (13) 3221- 3237
PubMed
Fini  MEParks  WCRinehart  WB  et al.  Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury. Am J Pathol 1996;149 (4) 1287- 1302
PubMed
Azar  DTPluznik  DJain  SKhoury  JM Gelatinase B and A expression after laser in situ keratomileusis and photorefractive keratectomy. Arch Ophthalmol 1998;116 (9) 1206- 1208
PubMed Link to Article
Ye  HQMaeda  MYu  FSAzar  DT Differential expression of MT1-MMP (MMP-14) and collagenase III (MMP-13) genes in normal and wounded rat corneas. Invest Ophthalmol Vis Sci 2000;41 (10) 2894- 2899
PubMed
Mulholland  BTuft  SJKhaw  PT Matrix metalloproteinase distribution during early corneal wound healing. Eye 2005;19 (5) 584- 588
PubMed Link to Article
Lu  PCYe  HMaeda  MAzar  DT Immunolocalization and gene expression of matrilysin during corneal wound healing. Invest Ophthalmol Vis Sci 1999;40 (1) 20- 27
PubMed
Williams  JMFini  MECousins  SWPepose  JS Corneal responses to infection. Krachmer  JHMannis  MJHolland  EJThe Cornea. Volume I Fundamentals of Cornea and External Disease. St Louis, MO Mosby1997;129- 162
Fini  MECook  JRMohan  R Proteolytic mechanisms in corneal ulceration and repair. Arch Dermatol Res 1998;290S12- S23
PubMed Link to Article
West-Mays  JAStrissel  KJSadow  PMFini  ME Competence for collagenase gene expression by tissue fibroblasts requires activation of an IL-1alpha autocrine loop. Proc Natl Acad Sci U S A 1995;92 (15) 6768- 6772
PubMed Link to Article
Mohan  RRinehart  WBBargagna-Mohan  PFini  ME Gelatinase B-LacZ transgenic mice: a model for mapping gelatinase B gene expression during developmental and injury-related tissue remodeling. J Biol Chem 1998;273 (40) 25903- 25914
PubMed Link to Article
Mohan  RSivak  JAshton  P  et al.  Curcuminoids inhibit the angiogenic response stimulated by FGF-2, including expression of Matrix Metalloproteinase Gelatinase B. J Biol Chem 2000;275 (14) 10405- 10412
PubMed Link to Article
Mohan  RChintala  SKJung  JC  et al.  Matrix metalloproteinase gelatinase B (MMP-9) regulates and effects epithelial regeneration. J Biol Chem 2002;277 (3) 2065- 2072
PubMed Link to Article
Sivak  JMWest-Mays  JAYee  AWilliams  TFini  ME Transcription factors Pax-6 and AP-2alpha interact to coordinate corneal epithelial repair by controlling expression of matrix metalloproteinase gelatinase B (MMP-9). Mol Cell Biol 2004;24 (1) 245- 257
PubMed Link to Article
Jung  JCHuh  MIFini  ME Constitutive collagenase-1 synthesis through MAPK pathways is mediated, in part, by endogenous IL-1alpha during fibrotic repair in corneal stroma. J Cell Biochem 2007;102 (2) 453- 462
PubMed Link to Article
Lyu  JJoo  CK Wnt-7a up-regulates matrix metalloproteinase-12 expression and promotes cell proliferation in corneal epithelial cells during wound healing. J Biol Chem 2005;280 (22) 21653- 21660
PubMed Link to Article
Berman  MDohlman  CHGnadinger  MDavison  P Characterization of collagenolytic activity in the ulcerating cornea. Exp Eye Res 1971;11 (2) 255- 257
PubMed Link to Article
Brown  DChwa  MEscobar  MKenney  MC Characterization of the major matrix degrading metalloproteinase of human corneal stroma: evidence for an enzyme/inhibitor complex. Exp Eye Res 1991;52 (1) 5- 16
PubMed Link to Article
Maguen  EZorapapel  NCZieske  JD  et al.  Extracellular matrix and matrix metalloproteinase changes in human corneas after complicated laser-assisted in situ keratomileusis (LASIK). Cornea 2002;21 (1) 95- 100
PubMed Link to Article
Hargrave  SLJung  JCFini  ME  et al.  Possible role of the vitamin E solubilizer in topical diclofenac on matrix metalloproteinase expression in corneal melting: an analysis of postoperative keratolysis. Ophthalmology 2002;109 (2) 343- 350
PubMed Link to Article
O'Brien  TPLi  QJSauerburger  FReviglio  VERana  TAshraf  MF The role of matrix metalloproteinases in ulcerative keratolysis associated with perioperative diclofenac use. Ophthalmology 2001;108 (4) 656- 659
PubMed Link to Article
Gross  JNagai  Y Specific degradation of the collagen molecule by tadpole collagenolytic enzyme. Proc Natl Acad Sci U S A 1965;54 (4) 1197- 1204
PubMed Link to Article
Gross  J How tadpoles lose their tails: path to discovery of the first matrix metalloproteinase. Matrix Biol 2004;23 (1) 3- 13
PubMed Link to Article
Itoi  MGnadinger  MCSlansky  HHFreeman  MIDohlman  CH Collagenase in the cornea. Exp Eye Res 1969;8 (3) 369- 373
PubMed Link to Article
Brown  SIWeller  CA Cell origin of collagenase in normal and wounded corneas. Arch Ophthalmol 1970;83 (1) 74- 77
PubMed Link to Article
Dohlman  CH The function of the corneal epithelium in health and disease: the Jonas S. Friedenwald Memorial Lecture. Invest Ophthalmol 1971;10 (6) 383- 407
PubMed
Berman  M The pathogenesis of corneal epithelial defects. Acta Ophthalmol Suppl 1989;19255- 64
PubMed
Fini  MEGirard  MT Expression of collagenolytic/gelatinolytic metalloproteinases by normal cornea. Invest Ophthalmol Vis Sci 1990;31 (9) 1779- 1788[published correction appears in Invest Ophthalmol Vis Sci. 1990;31(11):2229].
PubMed
Shapiro  SD Mighty mice: transgenic technology “knocks out” questions of matrix metalloproteinase function. Matrix Biol 1997;15 (8-9) 527- 533
PubMed Link to Article
Chen  LKato  TToshida  HNakamura  SMurakami  A Immunohistochemical characterization of epithelial cells implanted in the flap-stroma interface of the cornea. Jpn J Ophthalmol 2005;49 (2) 79- 83
PubMed Link to Article
Wilson  CLOuellette  AJSatchell  DP  et al.  Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 1999;286 (5437) 113- 117
PubMed Link to Article
Parks  WCLopez-Boado  YSWilson  CL Matrilysin in epithelial repair and defense. Chest 2001;120 (1) ((suppl)) 36S- 41S
PubMed Link to Article
Jester  JVPetroll  WMBarry  PACavanagh  HD Expression of α-smooth muscle (α-SM) actin during corneal stromal wound healing. Invest Ophthalmol Vis Sci 1995;36 (5) 809- 819
PubMed
Comaish  IFLawless  MA Progressive post-LASIK keratectasia: biomechanical instability or chronic disease process? J Cataract Refract Surg 2002;28 (12) 2206- 2213
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Light microscopy of laser-assisted in situ keratomileusis (LASIK) flaps (hematoxylin-eosin, original magnification × 200). Histopathologic findings of the peripheral LASIK wound margin regions (arrowheads) display varying healing modalities. A, “Normal healing” with good alignment of Bowman’s layer ends (patient 4R). B, Epithelial hyperplasia with depressed Bowman’s layer end (patient 3L). C, Epithelial ingrowth (patient 1). D, Bowman’s layer end curled inward with a flap retraction (patient 5R). E, Double-cut LASIK with the second cut deeper and wider (patient 10).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Immunofluorescence of a cornea after laser-assisted in situ keratomileusis complicated by an epithelial ingrowth (patient 1). A-C, Positive staining for matrix metalloproteinase 7 (B) and matrix metalloproteinase 9 (C) around epithelial cells trapped in the lamellar scar compared with the negative control (rabbit IgG) (A) (A and B, original magnification × 400; C, original magnification × 630). D, Discontinuous epithelial basement membrane laminin was observed (arrow) (original magnification × 630).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Immunofluorescence of double-cut laser-assisted in situ keratomileusis in patient 10. A, Negative control (rabbit IgG) (original magnification × 400). B, Positive staining for matrix metalloproteinase 9 was observed around some epithelial cells trapped within the peripheral scar of the first cut (original magnification × 630). C, Irregular epithelial basement membrane laminin was observed (original magnification × 400). D, Negative control (mouse IgG). Arrow points to the peripheral edge of the second cut (original magnification × 400). E and F, Cells positive for α–smooth muscle actin (arrowheads) were observed in the stroma (E, original magnification × 400; F, original magnification × 1000).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Immunofluorescence of the laser-assisted in situ keratomileusis flap margin of patient 5R with flap retraction. A-E, Positive staining for matrix metalloproteinase (MMP) 3 (B), MMP-7 (C), MMP-8 (D), and Mac-1 (CD11b) (arrows) (E) was observed within the margin defect compared with the negative control (rabbit IgG) (A). F and G, No MMP-9 staining (F) or continuous epithelial basement membrane laminin (G) were observed. I and H, Note the presence of α–smooth muscle actin (I) within the defect compared with the negative control (mouse IgG) (H) (A-I, original magnification × 400).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 3. Immunostaining Findings in the LASIK Wound Margin (Groups 1-4) and in the Control Group

References

Sandoval  HPde Castro  LEVroman  DTSolomon  KD Refractive Surgery Survey 2004. J Cataract Refract Surg 2005;31 (1) 221- 233
PubMed Link to Article
Fini  MEStramer  BM How the cornea heals: cornea-specific repair mechanisms affecting surgical outcomes. Cornea 2005;24 (8) ((suppl)) S2- S11
PubMed Link to Article
Wilson  SEMohan  RRHutcheon  AE  et al.  Effect of ectopic epithelial tissue within the stroma on keratocyte apoptosis, mitosis, and myofibroblast transformation. Exp Eye Res 2003;76 (2) 193- 201
PubMed Link to Article
Stramer  BMZieske  JDJung  JCAustin  JSFini  ME Molecular mechanisms controlling the fibrotic repair phenotype in cornea: implications for surgical outcomes. Invest Ophthalmol Vis Sci 2003;44 (10) 4237- 4246
PubMed Link to Article
Dawson  DGHolley  GPGeroski  DHWaring  GO  IIIGrossniklaus  HEEdelhauser  HF Ex vivo confocal microscopy of human LASIK corneas with histologic and ultrastructural correlation. Ophthalmology 2005;112 (4) 634- 644
PubMed Link to Article
Dawson  DGKramer  TRGrossniklaus  HEWaring  GO  IIIEdelhauser  HF Histologic, ultrastructural, and immunofluorescent evaluation of human laser-assisted in situ keratomileusis corneal wounds. Arch Ophthalmol 2005;123 (6) 741- 756
PubMed Link to Article
Schmack  IDawson  DGMcCarey  BEWaring  GO  IIIGrossniklaus  HEEdelhauser  HF Cohesive tensile strength of human LASIK wounds with histologic, ultrastructural, and clinical correlations. J Refract Surg 2005;21 (5) 433- 445
PubMed
Woessner  JF  Jr The matrix metalloproteinase family. Parks  WCMecham  RPMatrix Metalloproteinase. San Diego, CA Academic Press1998;300- 356
Page-McCaw  AEwald  AJWerb  Z Matrix metalloproteinases and the regulation of tissue remodeling. Nat Rev Mol Cell Biol 2007;8 (3) 221- 233
PubMed Link to Article
Brinckerhoff  CEMatrisian  LM Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 2002;3 (3) 207- 214
PubMed Link to Article
Nagase  HVisse  RMurphy  G Structure and function of matrix metalloproteinases and TIMPs [published online ahead of print January 5, 2006]. Cardiovasc Res 2006;69 (3) 562- 573
PubMed Link to Article
Puente  XSSanchez  LMOverall  CMLopez-Otin  C Human and mouse proteases: a comparative genomic approach. Nat Rev Genet 2003;4 (7) 544- 558
PubMed Link to Article
Somerville  RPOblander  SAApte  SS Matrix metalloproteinases: old dogs with new tricks [published online ahead of print May 29, 2003]. Genome Biol 2003;4 (6) 216
PubMed Link to Article
Overall  CMBlobel  CP In search of partners: linking extracellular proteases to substrates [published online ahead of print February 14, 2007]. Nat Rev Mol Cell Biol 2007;8 (3) 245- 257
PubMed Link to Article
Fini  MECook  JRMohan  RBrinckerhoff  CE Regulation of matrix metalloproteinase gene expression. Parks  WCMecham  RPMatrix Metalloproteinases. San Diego, CA Academic Press1998;300- 339
Sivak  JMFini  ME MMPs in the eye: emerging roles for matrix metalloproteinases in ocular physiology. Prog Retin Eye Res 2002;21 (1) 1- 14
PubMed Link to Article
Parks  WC Matrix metalloproteinases in repair. Wound Repair Regen 1999;7 (6) 423- 432
PubMed Link to Article
Lim  MGoldstein  MHTuli  SSchultz  GS Growth factor, cytokine and protease interactions during corneal wound healing. Ocul Surf 2003;1 (2) 53- 65
PubMed Link to Article
Matsubara  MGirard  MTKublin  CLCintron  CFini  ME Differential roles for two gelatinolytic enzymes of the matrix metalloproteinase family in the remodeling cornea. Dev Biol 1991;147 (2) 425- 439
PubMed Link to Article
Girard  MTMatsubara  MKublin  CTessier  MJCintron  CFini  ME Stromal fibroblasts synthesize collagenase and stromelysin during long-term tissue remodeling. J Cell Sci 1993;1041001- 1011
PubMed
Matsubara  MZieske  JDFini  ME Mechanism of basement membrane dissolution preceding corneal ulceration. Invest Ophthalmol Vis Sci 1991;32 (13) 3221- 3237
PubMed
Fini  MEParks  WCRinehart  WB  et al.  Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury. Am J Pathol 1996;149 (4) 1287- 1302
PubMed
Azar  DTPluznik  DJain  SKhoury  JM Gelatinase B and A expression after laser in situ keratomileusis and photorefractive keratectomy. Arch Ophthalmol 1998;116 (9) 1206- 1208
PubMed Link to Article
Ye  HQMaeda  MYu  FSAzar  DT Differential expression of MT1-MMP (MMP-14) and collagenase III (MMP-13) genes in normal and wounded rat corneas. Invest Ophthalmol Vis Sci 2000;41 (10) 2894- 2899
PubMed
Mulholland  BTuft  SJKhaw  PT Matrix metalloproteinase distribution during early corneal wound healing. Eye 2005;19 (5) 584- 588
PubMed Link to Article
Lu  PCYe  HMaeda  MAzar  DT Immunolocalization and gene expression of matrilysin during corneal wound healing. Invest Ophthalmol Vis Sci 1999;40 (1) 20- 27
PubMed
Williams  JMFini  MECousins  SWPepose  JS Corneal responses to infection. Krachmer  JHMannis  MJHolland  EJThe Cornea. Volume I Fundamentals of Cornea and External Disease. St Louis, MO Mosby1997;129- 162
Fini  MECook  JRMohan  R Proteolytic mechanisms in corneal ulceration and repair. Arch Dermatol Res 1998;290S12- S23
PubMed Link to Article
West-Mays  JAStrissel  KJSadow  PMFini  ME Competence for collagenase gene expression by tissue fibroblasts requires activation of an IL-1alpha autocrine loop. Proc Natl Acad Sci U S A 1995;92 (15) 6768- 6772
PubMed Link to Article
Mohan  RRinehart  WBBargagna-Mohan  PFini  ME Gelatinase B-LacZ transgenic mice: a model for mapping gelatinase B gene expression during developmental and injury-related tissue remodeling. J Biol Chem 1998;273 (40) 25903- 25914
PubMed Link to Article
Mohan  RSivak  JAshton  P  et al.  Curcuminoids inhibit the angiogenic response stimulated by FGF-2, including expression of Matrix Metalloproteinase Gelatinase B. J Biol Chem 2000;275 (14) 10405- 10412
PubMed Link to Article
Mohan  RChintala  SKJung  JC  et al.  Matrix metalloproteinase gelatinase B (MMP-9) regulates and effects epithelial regeneration. J Biol Chem 2002;277 (3) 2065- 2072
PubMed Link to Article
Sivak  JMWest-Mays  JAYee  AWilliams  TFini  ME Transcription factors Pax-6 and AP-2alpha interact to coordinate corneal epithelial repair by controlling expression of matrix metalloproteinase gelatinase B (MMP-9). Mol Cell Biol 2004;24 (1) 245- 257
PubMed Link to Article
Jung  JCHuh  MIFini  ME Constitutive collagenase-1 synthesis through MAPK pathways is mediated, in part, by endogenous IL-1alpha during fibrotic repair in corneal stroma. J Cell Biochem 2007;102 (2) 453- 462
PubMed Link to Article
Lyu  JJoo  CK Wnt-7a up-regulates matrix metalloproteinase-12 expression and promotes cell proliferation in corneal epithelial cells during wound healing. J Biol Chem 2005;280 (22) 21653- 21660
PubMed Link to Article
Berman  MDohlman  CHGnadinger  MDavison  P Characterization of collagenolytic activity in the ulcerating cornea. Exp Eye Res 1971;11 (2) 255- 257
PubMed Link to Article
Brown  DChwa  MEscobar  MKenney  MC Characterization of the major matrix degrading metalloproteinase of human corneal stroma: evidence for an enzyme/inhibitor complex. Exp Eye Res 1991;52 (1) 5- 16
PubMed Link to Article
Maguen  EZorapapel  NCZieske  JD  et al.  Extracellular matrix and matrix metalloproteinase changes in human corneas after complicated laser-assisted in situ keratomileusis (LASIK). Cornea 2002;21 (1) 95- 100
PubMed Link to Article
Hargrave  SLJung  JCFini  ME  et al.  Possible role of the vitamin E solubilizer in topical diclofenac on matrix metalloproteinase expression in corneal melting: an analysis of postoperative keratolysis. Ophthalmology 2002;109 (2) 343- 350
PubMed Link to Article
O'Brien  TPLi  QJSauerburger  FReviglio  VERana  TAshraf  MF The role of matrix metalloproteinases in ulcerative keratolysis associated with perioperative diclofenac use. Ophthalmology 2001;108 (4) 656- 659
PubMed Link to Article
Gross  JNagai  Y Specific degradation of the collagen molecule by tadpole collagenolytic enzyme. Proc Natl Acad Sci U S A 1965;54 (4) 1197- 1204
PubMed Link to Article
Gross  J How tadpoles lose their tails: path to discovery of the first matrix metalloproteinase. Matrix Biol 2004;23 (1) 3- 13
PubMed Link to Article
Itoi  MGnadinger  MCSlansky  HHFreeman  MIDohlman  CH Collagenase in the cornea. Exp Eye Res 1969;8 (3) 369- 373
PubMed Link to Article
Brown  SIWeller  CA Cell origin of collagenase in normal and wounded corneas. Arch Ophthalmol 1970;83 (1) 74- 77
PubMed Link to Article
Dohlman  CH The function of the corneal epithelium in health and disease: the Jonas S. Friedenwald Memorial Lecture. Invest Ophthalmol 1971;10 (6) 383- 407
PubMed
Berman  M The pathogenesis of corneal epithelial defects. Acta Ophthalmol Suppl 1989;19255- 64
PubMed
Fini  MEGirard  MT Expression of collagenolytic/gelatinolytic metalloproteinases by normal cornea. Invest Ophthalmol Vis Sci 1990;31 (9) 1779- 1788[published correction appears in Invest Ophthalmol Vis Sci. 1990;31(11):2229].
PubMed
Shapiro  SD Mighty mice: transgenic technology “knocks out” questions of matrix metalloproteinase function. Matrix Biol 1997;15 (8-9) 527- 533
PubMed Link to Article
Chen  LKato  TToshida  HNakamura  SMurakami  A Immunohistochemical characterization of epithelial cells implanted in the flap-stroma interface of the cornea. Jpn J Ophthalmol 2005;49 (2) 79- 83
PubMed Link to Article
Wilson  CLOuellette  AJSatchell  DP  et al.  Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 1999;286 (5437) 113- 117
PubMed Link to Article
Parks  WCLopez-Boado  YSWilson  CL Matrilysin in epithelial repair and defense. Chest 2001;120 (1) ((suppl)) 36S- 41S
PubMed Link to Article
Jester  JVPetroll  WMBarry  PACavanagh  HD Expression of α-smooth muscle (α-SM) actin during corneal stromal wound healing. Invest Ophthalmol Vis Sci 1995;36 (5) 809- 819
PubMed
Comaish  IFLawless  MA Progressive post-LASIK keratectasia: biomechanical instability or chronic disease process? J Cataract Refract Surg 2002;28 (12) 2206- 2213
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

905 Views
3 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs