CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling.

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/ß1 and αV/ß5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.

PTP1B mediates the inhibitory effect of MFGE8 on insulin signaling through the ß5 integrin.

Integrins are cell adhesion receptors that dimerize to mediate cell-cell interactions and regulate processes, including proliferation, inflammation, and tissue repair. The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvß5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, integrin ß5 complexes with the insulin receptor beta (IRß) in skeletal muscle, resulting in dephosphorylation of IRß and reduction of insulin-stimulated glucose uptake. Here, we investigate the mechanism by which the interaction between ß5 and IRß impacts IRß phosphorylation status. We show in in vitro and in vivo in skeletal muscle in mice that antibody-mediated blockade of the ß5 integrin inhibits and recombinant MFGE8 promotes PTP1B binding to and dephosphorylation of IRß resulting in increased or reduced insulin-stimulated glucose uptake, respectively. The ß5-PTP1B complex is recruited by MFGE8 to IRß leading to termination of canonical insulin signaling. ß5 blockade enhances insulin-stimulated glucose uptake in wildtype but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and ß5 in regulating insulin signaling.

Autoregulation of insulin receptor signaling through MFGE8 and the αvß5 integrin.

The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvß5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/ß5 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cell-surface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the αvß5 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/ß5 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the αvß5 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity.

Ultrasound-assisted ocular drug delivery: A review of current evidence.

Efficient ocular drug delivery is a challenging clinical problem with various therapeutic options but no clearly preferred methodology. Given the ubiquity of ultrasound as a diagnostic technique, the safety profile of ultrasound in an ocular context, and the prospect of custom-made ultrasound-sensitive contrast agents, ultrasound presents an attractive ocular drug delivery modality. In this review, we evaluate our present understanding of ultrasound as it relates to ocular drug delivery and significant knowledge gaps in the field. In doing so, we hope to call attention to a potentially novel drug delivery pathway that could be manipulated to treat or cure ocular diseases.

You Say You Want a Resolution (of Fibrosis).

In pathological fibrosis, aberrant tissue remodeling with excess extracellular matrix leads to organ dysfunction and eventual morbidity. Diseases of fibrosis create significant global health and economic burdens and are often deadly. Although fibrosis has traditionally been thought of as an irreversible process, a growing body of evidence demonstrates that organ fibrosis can reverse in certain circumstances, especially if an underlying cause of injury can be removed. This body of evidence has uncovered more and more contributors to persistent and nonresolving tissue fibrosis. Here, we review the present knowledge on resolution of organ fibrosis and restoration of near-normal tissue architecture. We emphasize three critical areas of tissue homeostasis that are necessary for fibrosis resolution, namely, the elimination of matrix-producing cells, the clearance of excess matrix, and the regeneration of normal tissue constituents. In so doing, we also highlight how profibrotic pathways interact with one another and where there may be therapeutic opportunities to intervene and remediate pathological persistent fibrosis.

Efficacy of a novel oxygen scavenger mask in reducing local oxygen concentrations below the surgical fire risk threshold: an experimental proof-of-concept study.

BACKGROUND: This study aims to evaluate the efficacy of an oxygen scavenging mask device in reducing local oxygen concentrations from nasal cannula ventilation compared to a standard open facial surgical field. METHODS: This is a controlled experiment using a custom-fabricated silicone midfacial oxygen scavenging device, SimMan airway management trainer manikin (Laerdal Medical, Stavanger, Norway), handheld oxygen detector (Forensics Detectors, Los Angeles, United States) and oxygen from a Datex Ohmeda Aisys Carestation anesthesia unit (GE HealthCare, Chicago, United States). Oxygen concentrations were measured at 18 facial landmarks (Fig. 1) with nasal cannula flow of 2, 4, and 6 L/min of 100% FiO2 in both masked and unmasked conditions (Fig. 2). RESULTS: The mean oxygen concentration in the facial surgical field was 20.95% with the scavenger mask and 24.8% without (P < 0.001; two-tailed paired t-test). The unmasked condition was associated with suprathreshold oxygen concentration levels at 13 of 18 facial landmarks (Table 1). The device significantly reduced local oxygen concentration at 16 of 18 facial landmarks (Table 1). The device provided safe oxygen concentration levels at all three flow rates, and measured oxygen concentrations directly correlated with oxygen flow rate in the unmasked condition (Table 2). CONCLUSIONS: An oxygen scavenger mask device reduced local oxygen concentrations from nasal cannula ventilation to below the 23% fire threshold in the entire facial surgical field external to the mask in these experiments. The device may reduce intraoperative fire risk in patients that require supplementary oxygen during surgery.

Clinical Validation of a Handheld Deep Learning Tool for Identification of Glaucoma Medications.

Purpose: To validate a convolutional neural network (CNN)-based smartphone application for the identification of glaucoma eye drop medications in patients with normal and impaired vision. Methods: Sixty-eight patients with visual acuity (VA) of 20/70 or worse in at least one eye who presented to an academic glaucoma clinic from January 2021 through August 2022 were included. Non-English-speaking patients were excluded. Enrolled subjects participated in an activity in which they identified a predetermined and preordered set of six topical glaucoma medications, first without the CNN and then with the CNN for a total of six sequential measurements per subject. Responses to a standardized survey were collected during and after the activity. Primary quantitative outcomes were medication identification accuracy and time. Primary qualitative outcomes were subjective ratings of ease of smartphone application use. Results: Topical glaucoma medication identification accuracy (OR = 12.005, P < 0.001) and time (OR = 0.007, P < 0.001) both independently improved with CNN use. CNN use significantly improved medication accuracy in patients with glaucoma (OR = 4.771, P = 0.036) or VA ≤ 20/70 in at least one eye (OR = 4.463, P = 0.013) and medication identification time in patients with glaucoma (OR = 0.065, P = 0.017). CNN use had a significant positive association with subject-reported ease of medication identification (X2(1) = 66.117, P < 0.001). Conclusion: Our CNN-based smartphone application is efficacious at improving glaucoma eye drop identification accuracy and time. This tool can be used in the outpatient setting to avert preventable vision loss by improving medication adherence in patients with glaucoma.

Effective low-cost pediatric vision screening by naive nonophthalmic examiners using the 'Arclight' device.

PURPOSE: To explore whether a low-cost ophthalmoscope (Arclight) can be used by naive nonophthalmic examiners to effectively screen for pediatric eye disease. METHODS: Fifty-four children (108 eyes) were examined by five medical students using an Arclight. Gold standard examination was performed by an ophthalmologist using a slit lamp and indirect ophthalmoscope. Examinations performed included ophthalmoscopy of the optic disc, estimation of the cup-to-disc ratio (CDR), corneal light reflex test (CRT), Bruckner's reflex test (BRT), and evaluation of refractive error. We determined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the nonophthalmologist's Arclight exam compared to the gold standard findings of comprehensive evaluation by pediatric ophthalmologists. RESULTS: Using the Arclight, the optic nerve exam was successfully completed in 65% of patients. CDRs above and below 0.5 could be determined with 66.7% sensitivity and 84.4% specificity. Arclight CRT measurements were significant (P < .00001) predictors of strabismus, with 80% sensitivity, 95.1%, specificity, 80% PPV, and 95.1% NPV. BRT was not a significant predictor of amblyopia, with a 34.6% sensitivity, 85.7% specificity, 69.2% PPV, and 58.5% NPV. Refractive error was estimated with a success rate of 81% for emmetropia, 38% for myopia, and 21% for hyperopia. The Arclight ease-of-use was rated on average as 4.4 (SD = 0.9) on a scale of 1 to 5, with 1 being the hardest and 5 being the easiest. CONCLUSIONS: Our study shows the Arclight as an affordable and effective alternative to the traditional ophthalmoscope for assessing eye disease in children. This device can improve eye health services in under-resourced regions.

Three cases of recalcitrant Paecilomyces keratitis in Southern California within a short period.

BACKGROUND: The aim of this report is to describe the risk factors, clinical course, and characteristics of three cases of Paecilomyces keratitis presenting concurrently within three months in the same location. We used in vivo confocal microscopy and histopathology to corroborate our clinical findings. OBSERVATIONS: Three eyes of three elderly patients with culture-proven Paecilomyces keratitis were included in this series. These patients resided within a 15-mile radius and presented to a tertiary care eye institute in Southern California between February and April 2022. All three eyes experienced a prolonged, recalcitrant course with recurrence of keratitis in donor corneal tissue despite antifungal therapy and multiple therapeutic penetrating keratoplasties. In vivo confocal microscopy, histopathology, and microbiologic findings corroborated the diagnosis of fungal keratitis with Paecilomyces. With surgical intervention and extensive medical therapy, all three cases resolved after the addition of oral Posaconazole. CONCLUSIONS: Paecilomyces is a rare cause of infectious keratitis. Herein we report three similar cases in elderly patients. All had prolonged, recalcitrant infections that required multiple treatment modalities. Our cases, which were supported by in vivo confocal microscopy and histopathology, highlight the importance of timely and aggressive therapy to prevent recurrence.

Interventions to Reduce Surgical Waste Burden: A Systematic Review.

Background: Operating suites are significant drivers of waste, pollution, and costs. Surgeons can help fight the climate crisis by implementing innovative strategies aimed at mitigating the environmental impact of surgical procedures and decreasing operational costs, and moving toward a more sustainable healthcare system. This study aims to review the literature describing interventions that reduce surgical waste. Methods: PubMed, Cochrane, and Embase were searched. Studies reporting interventions to reduce operative waste, including emissions, energy, trash, and other, were included. Case reports, opinion-based reports, reviews, and meta-analyses were excluded. Study quality was rated using MINORS and Jadad scales. Data were extracted from each study to calculate waste on a per case basis. Narrative review of studies was performed rather than meta-analysis. Results: The search yielded 675 unique hits, of which 13 (level of evidence: I-III) met inclusion criteria. Included studies were categorized by intervention type in relation to the operating and procedure room. Three studies evaluated provider education initiatives, three evaluated setup of instruments, two evaluated single-use items, four evaluated technique changes, and one evaluated surgical venue. Seven studies reported significant reductions in disposable surgical waste throughput, and seven reported significant reductions in cost. Conclusions: The results of this systemic review demonstrated the effectiveness of surgical waste reduction initiatives in reducing waste volume, cost, and carbon emissions. Within plastic surgery, minimal surgical packs resulted in reduced gross waste and cost while promoting patient satisfaction in hand surgery, supporting the continued development and implementation of such initiatives in a surgical context.

Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover.

Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, here we execute unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discover a mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism appears to be dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of this protein. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus, we describe cell-autonomous, rheostatic collagen clearance as an important pathway of tissue homeostasis.

Surgical Care Through a Community Free Clinic-Ambulatory Surgical Center Partnership.

BACKGROUND: Disparities secondary to underinsurance present throughout the surgical care continuum. Community free clinics are uniquely capable to provide health care services to the medically underserved, but surgery often falls outside their scope of care. METHODS: Retrospective chart review was conducted on consecutive community free clinic patients receiving free surgical services via referral to a partnering ambulatory surgery center between March 2016 and September 2021. Those with documented contact information were recruited 1-3 years post-procedure for long-term quality-of-life (LTQOL) outcomes assessment via modified Veterans RAND 12-item health survey. RESULTS: Of 142 included patients, 95.7% identified as Hispanic/Latino and 75.6% were uninsured. Twelve patients had cancerous or precancerous lesions detected and/or removed through diagnostic or definitive procedures. 3.5% experienced postoperative complication including bacterial (n = 2) or fungal (n = 1) surgical site infection and wound dehiscence (n = 2). With a 48.9% response rate, no significant differences in sociodemographic or clinical characteristics were found between surveyed vs non-surveyed patients. Of surveyed patients, 59.7% and 52.2% reported pre-/post-operative improvement in physical health and emotional health, respectively. DISCUSSION: Free diagnostic screening procedures provided timely diagnoses while free definitive surgeries safely and positively impacted long-term patient-reported physical health. Longitudinal, multidisciplinary follow-up and social support may be warranted to concurrently improve emotional and mental health in similarly underinsured populations.

Applications of Ocular Point-of-Care Ultrasound for Optic Nerve Sheath Assessment in the Emergency Setting: A Systematic Review.

Objective: To evaluate the current body of literature pertaining to the use of ocular point-of-care ultrasound (POCUS) in the emergency department. Methods: A comprehensive literature search was conducted on SCOPUS, Web of Science, MEDLINE, and Cochrane CENTRAL. Inclusion criteria included studies written in English only and primary clinical studies involving ocular POCUS scans in an emergency department setting. Exclusion criteria included non-primary studies (e.g. reviews or case reports), studies written in a non-English language, non-human studies, studies performed in a non-emergency setting, studies involving non-POCUS ocular ultrasound modalities, or studies published outside of the last decade. Data extraction was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Results: The initial search yielded 391 results with 153 duplicates. Of the remaining 238 studies selected for retrieval and screening, 24 met inclusion criteria. These 24 included studies encompassed 2448 patients across prospective, retrospective, cross sectional, and case series study designs. We found that a majority of included studies focus on the use of POCUS in the emergency department to measure ONSD as a proxy for papilledema and metabolic aberrations, while a minority use ocular POCUS to assist in the diagnosis of orbital fractures or posterior segment pathology. Conclusion: The vast majority of articles investigating the use of ocular POCUS in recent years emphasize its utility in measuring ONSD and fluctuations in intracranial pressure, though additional outcomes of interest include posterior segment, orbit, and globe pathology.

Anterior Chamber Washout During Ahmed Valve Glaucoma Surgery Reduces the Incidence of Hypertensive Phase.

PRCIS: Intraoperative anterior chamber (AC) washout reduces the odds of hypertensive phase (HP) by 95% compared with those not receiving washout during Ahmed glaucoma implant (AGI), suggesting AC washout is an effective prophylaxis for postoperative HP. PURPOSE: To characterize the incidence of postoperative HP in patients receiving AC washout at the time of AGI. PATIENTS AND METHODS: A total of 24 patients with medically refractory glaucoma who underwent AGI surgery at a tertiary academic medical center in Southern California from December 2018 through March 2021 were included in this retrospective comparative case series. Patients who received a pediatric implant and underwent concurrent intraocular surgery or did not complete a minimum of 6 months of follow-up were excluded. Nine patient's eyes received AC washout and 15 controls that were analyzed through 6 months postprocedure. HP was defined as intraocular pressure (IOP) above 21 mm Hg within 6 months postprocedure with maximum tolerated medical therapy. AC washout was performed by irrigating the AC with a 5 mL balanced salt solution before placing the tube of the AGI into the AC. The rate of postoperative HP, defined as peak IOP >21 mm Hg, at 6 months follow-up, was observed as the primary outcome measure. RESULTS: Patients included in the study had a high mean preoperative IOP ( X̅ = 44.11, SD = 13.85). There were no baseline differences between the washout and control groups. The odds of HP were significantly reduced (odds ratio: 0.050; 95% CI: 0.004, 0.706; P = 0.027) for patients who underwent intraoperative AC washout compared with those who did not. Bivariate analysis of subject baseline characteristics revealed that only washout status was significantly different in subjects with HP compared with subjects without HP ( P = 0.015). A multivariate logistic regression model using washout status and autoimmune conditions as covariates was significant in predicting HP ( X2 (2) = 12.337, P = 0.002), with washout as a significant predictor when controlling for autoimmune comorbidities ( P = 0.027). CONCLUSIONS: AC washout significantly decreases the odds of HP after AGI surgery. AC washout with balanced salt solution adds minimal time and risks to surgery and therefore may be an effective adjunct during AGI placement.

The role of intrapartum fetal head compression in neonatal retinal hemorrhage.

PURPOSE: Neonatal retinal hemorrhage is a common finding in newborns, but the underlying mechanisms are not fully understood. A computational simulation was designed to study the events taking place in the eye and orbit when the head is compressed as the neonate passes through the birth canal. METHODS: A finite element model of the eye, optic nerve sheath, and orbit was simulated and subjected to forces mimicking rises in intracranial pressure (ICP) associated with maternal contractions during normal vaginal delivery. Resulting changes in intraocular pressure (IOP), pressure in the optic nerve sheath, and stress within the sclera and retina were measured. RESULTS: During contractions, increased ICP was transmitted to the orbit, globe, and optic nerve sheath. IOP rose by 2.71 kPa near the posterior pole. Pressure at the center of the optic nerve sheath rose by 7.31 kPa and up to 9.30 kPa at its interface with the sclera. Stress in the retina was highest near the optic disk and reached 10.93, 10.99, and 13.28 kPa in the preretinal, intraretinal, and subretinal layers, respectively. Stress in the sclera peaked at 12.76 kPa. CONCLUSIONS: Increasing ICP associated with natural vaginal delivery increases intraorbital pressure, which applies stress to the retina. Associated retinal deformation may cause tearing of the retinal vasculature. Increased pressure within the optic nerve sheath may occlude the central retinal vein, resulting in outflow obstruction and subsequent rupture. Forces accumulated near the optic disk, likely accounting for the tendency of neonatal retinal hemorrhage to occur posteriorly.

MFGE8 inhibits insulin signaling through PTP1B.

The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvß5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, ß5 complexes with the insulin receptor beta (IRß) in skeletal muscle resulting in dephosphorylation of IRß and reduction of insulin-stimulated glucose uptake. Here we investigate the mechanism by which the interaction between ß5 and IRß impacts IRß phosphorylation status. We show that ß5 blockade inhibits and MFGE8 promotes PTP1B binding to and dephosphorylation of IRß resulting in reduced or increased insulin-stimulated myotube glucose uptake respectively. The ß5-PTP1B complex is recruited by MFGE8 to IRß leading to termination of canonical insulin signaling. ß5 blockade enhances insulin-stimulated glucose uptake in wild type but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and ß5 in regulating insulin signaling.

MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes.

Enterocytes modulate the extent of postprandial lipemia by storing dietary fats in cytoplasmic lipid droplets (cLDs). We have previously shown that the integrin ligand MFGE8 links absorption of dietary fats with activation of triglyceride (TG) hydrolases that catabolize cLDs for chylomicron production. Here, we identify CES1D as the key hydrolase downstream of the MFGE8-αvß5 integrin pathway that regulates catabolism of diet-derived cLDs. Mfge8 knockout (KO) enterocytes have reduced CES1D transcript and protein levels and reduced protein levels of the transcription factor HNF4γ. Both Ces1d and Hnf4γ KO mice have decreased enterocyte TG hydrolase activity coupled with retention of TG in cLDs. Mechanistically, MFGE8-dependent fatty acid uptake through CD36 stabilizes HNF4γ protein level; HNF4γ then increases Ces1d transcription. Our work identifies a regulatory network that regulates the severity of postprandial lipemia by linking dietary fat absorption with protein stabilization of a transcription factor that increases expression of hydrolases responsible for catabolizing diet-derived cLDs.

Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover.

Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, we executed unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discovered a previously unappreciated mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism is dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of SEL1L. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus cell-autonomous, rheostatic collagen clearance is a previously unidentified pathway of tissue homeostasis.

Age-dependent regulation of cell-mediated collagen turnover.

Although aging represents the most important epidemiologic risk factor for fibrotic disease, the reasons for this are incompletely understood. Excess collagen deposition in tissues is the sine qua non of tissue fibrosis and can be viewed as an imbalance between collagen production and collagen degradation. Yet we still lack a detailed understanding of the changes that take place during development, maturation, and aging in extracellular matrix (ECM) dynamics. Resolution of fibrosis is impaired in aging, and this impairment may explain why age is the most important risk factor for fibrotic diseases, such as idiopathic pulmonary fibrosis. However, ECM dynamics and impaired resolution of fibrosis in aging remain understudied. Here we show that cell-mediated collagen uptake and degradation are diminished in aged animals and this finding correlates with downregulation of the collagen endocytic receptor mannose receptor, C-type 2 (Mrc2). We identify myeloid zinc finger-1 as a potentially novel transcriptional regulator of Mrc2, and both this transcription factor and Mrc2 are downregulated in multiple tissues and organisms in an age-dependent manner. Thus, cell-mediated degradation of collagen is an essential process that promotes resolution of fibrosis, and impairment in this process contributes to age-related fibrosis.