Compromised Tissue Repair Research Articles

Impact of diabetes mellitus on endodontic treatment outcomes

Diabetes mellitus (DM) is a chronic metabolic disorder that affects various systemic functions, including oral health. Its impact on endodontic treatment outcomes has become a significant concern for dental practitioners. The relationship between DM and endodontic outcomes is complex, involving several pathophysiological mechanisms. Hyperglycemia leads to the formation of advanced glycation end-products, causing vascular dysfunction and impaired blood supply to the pulp, which exacerbates pulpal inflammation and increases the risk of necrosis. Additionally, chronic low-grade inflammation and an impaired immune response in diabetic patients contribute to a higher susceptibility to infections, delayed healing, and compromised tissue repair after endodontic procedures. Diabetic patients often experience lower success rates and prolonged recovery following endodontic treatment due to these systemic challenges. Reduced bone healing, persistent periapical lesions, and altered microbial flora are common complications that can hinder treatment success. Effective management of endodontic treatment in diabetic patients requires a multifaceted approach that includes strict glycemic control, the use of enhanced antimicrobial strategies, and the adoption of minimally invasive techniques to reduce tissue trauma. Additionally, patient education and close monitoring of the healing process are essential for minimizing complications. Understanding the pathophysiological interactions between diabetes and pulpal inflammation, as well as the factors that influence healing and success rates, is crucial for optimizing endodontic care in diabetic patients. By addressing both systemic and local factors, dental practitioners can improve the prognosis of endodontic treatment and ensure better outcomes for patients with diabetes. Ongoing research into the mechanisms underlying these complications will further enhance the ability of clinicians to manage endodontic cases effectively in this growing patient population.

Dietary Iron Is Necessary to Support Proliferative Regeneration after Intestinal Injury

BackgroundTissue repair and regeneration in the gastrointestinal system are crucial for maintaining homeostasis, with the process relying on intricate cellular interactions and affected by micro- and macro-nutrients. Iron, essential for various biological functions, plays a dual role in tissue healing by potentially causing oxidative damage and participating in anti-inflammatory mechanisms, underscoring its complex relationship with inflammation and tissue repair. ObjectiveThe study aimed to elucidate the role of low dietary iron in gastrointestinal tissue repair. MethodsWe utilized quantitative iron measurements to assess iron levels in inflamed regions of patients with ulcerative colitis and Crohn’s disease. In addition, 3 mouse models of gastrointestinal injury/repair (dextran sulfate sodium-induced colitis, radiation injury, and wound biopsy) were used to assess the effects of low dietary iron on tissue repair. ResultsWe found that levels of iron in inflamed regions of both patients with ulcerative colitis and Crohn’s disease are elevated. Similarly, during gastrointestinal repair, iron levels were found to be heightened, specifically in intestinal epithelial cells across the 3 injury/repair models. Mice on a low-iron diet showed compromised tissue repair with reduced proliferation. In standard diet, epithelial cells and the stem cell compartment maintain adequate iron stores. However, during a period of iron deficiency, epithelial cells exhaust their iron reserves, whereas the stem cell compartments maintain their iron pools. During injury, when the stem compartment is disrupted, low iron levels impair proliferation and compromise repair mechanisms. ConclusionsLow dietary iron impairs intestinal repair through compromising the ability of epithelial cells to aid in intestinal proliferation.

Semaphorins: Missing Signals in Age-dependent Alteration of Neuromuscular Junctions and Skeletal Muscle Regeneration.

Skeletal muscle is characterized by a remarkable capacity to rearrange after physiological changes and efficiently regenerate. However, during aging, extensive injury, or pathological conditions, the complete regenerative program is severely affected, with a progressive loss of muscle mass and function, a condition known as sarcopenia. The compromised tissue repair program is attributable to the gradual depletion of stem cells and to altered regulatory signals. Defective muscle regeneration can severely affect re-innervation by motor axons, and neuromuscular junctions (NMJs) development, ultimately leading to skeletal muscle atrophy. Defects in NMJ formation and maintenance occur physiologically during aging and are responsible for the pathogenesis of several neuromuscular disorders. However, it is still largely unknown how neuromuscular connections are restored on regenerating fibers. It has been suggested that attractive and repelling signals used for axon guidance could be implicated in this process; in particular, guidance molecules called semaphorins play a key role. Semaphorins are a wide family of extracellular regulatory signals with a multifaceted role in cell-cell communication. Originally discovered as axon guidance factors, they have been implicated in cancer progression, embryonal organogenesis, skeletal muscle innervation, and other physiological and developmental functions in different tissues. In particular, in skeletal muscle, specific semaphorin molecules are involved in the restoration and remodeling of the nerve-muscle connections, thus emphasizing their plausible role to ensure the success of muscle regeneration. This review article aims to discuss the impact of aging on skeletal muscle regeneration and NMJs remodeling and will highlight the most recent insights about the role of semaphorins in this context.

Influence of subscapularis stiffness with glenosphere lateralization on physiological external rotation limits after reverse shoulder arthroplasty.

Repair of the subscapularis following reverse shoulder arthroplasty (RSA) remains a controversial topic among surgeons. Poor rotator cuff muscle quality is associated with increased musculotendinous stiffness, and the subsequent effect of compromised tissue repair on RSA functional outcomes remains unclear. The objective was to investigate the influence of subscapularis stiffness together with glenoid component lateralization on pre- and postimpingement joint mechanics during external rotation after RSA. A validated finite element model incorporating the Zimmer Trabecular Metal reverse system was used. The deltoid and subscapularis tendon were tensioned and wrapped around the joint prior to controlled shoulder external rotation. Baseline subscapularis stiffness, determined from cadaveric testing, was varied to 80%, 120% and 140% of baseline, to simulate a range of pliability associated with fatty infiltration and fibrosis. We evaluated the effects of varying subscapularis stiffness and the corresponding variation in joint tension with varying glenosphere lateralization (2, 4, and 10 mm) on the torque required to externally rotate the shoulder and the impingement/subluxation risk. Prior to any impingement, the torques required to externally rotate the shoulder ranged from 22-47 Nm across the range of parameters studied, with the greatest torques required for the 10-mm glenosphere lateralization. The impact of increasing subscapularis stiffness on torque requirements was most pronounced at the 10-mm lateralization, as well. A 20% increase in subscapularis stiffness necessitated a 7%-14% increase in preimpingement torque, whereas a 40% stiffness increase was associated with a 12%-27% increase in torque. Torque was proportional to lateralization. When lateralization was increased from 2 to 4 mm, the preimpingement torque increased by 10%-13%, whereas a 10-mm lateralization necessitated a 35%-62% torque increase relative to 2 mm of lateralization. Increased subscapularis stiffness did not limit impingement-free range of motion or substantially decrease postimpingement subluxation in this model. Mechanical gains achieved through lateralization may be hindered by increased torque demands, especially when a stiffer subscapularis is repaired. As lateralization increases subscapularis tension, greater torque is required to externally rotate the shoulder. The torque required for external rotation has been reported between 15-50 Nm. Subscapularis repair with the simulated increases in stiffness requires relative increases in torque that the reconstructed shoulder may not be able to physically produce to rotate the glenohumeral joint, particularly at 10-mm lateralization. These results suggest that subscapularis repair may not be indicated in cases where a lateralized glenoid component is used and the subscapularis is compromised.

Influence of the treatment with the antineoplastic agents 5-fluorouracil and cisplatin on the severity of experimental periodontitis in rats.

The determination on how antineoplastic agents interfere on the progression of periodontitis is critical for improvement and even development of novel therapeutic approaches for periodontal management. This study evaluated the influence of chemotherapy with 5-fluorouracil (5-FU) or cisplatin (CIS) on healthy periodontal tissues and on the progression of experimental periodontitis (EP). One hundred forty-four male rats were divided into six groups (n = 24). Each group was treated with physiological saline solution (PSS) 0.9%, 5-FU, or CIS. Experimental periodontitis (EP) was induced by ligature placement. Animals were euthanized at 7, 15, and 30days after treatment. Data were statistically analyzed (p ≤ 0.05). The groups with EP and treated with 5-FU or CIS showed lower percentage of bone volume in the furcation region and higher percentage of alveolar bone loss, higher number of TRAP-positive cells, and lower number of PCNA-positive cells when compared group with EP and treated with PSS (p ≤ 0.05). Groups with EP and treated with 5-FU or CIS showed high immunolabelling pattern of RANKL, TNF-α, and IL-1β, moderate of BAX, and low of HIF-1α. Histological analysis showed severe tissue breakdown in the groups with EP and treated with 5-FU or CIS. Chemotherapy with antineoplastic agents 5-FU and CIS increased the intensity and duration of the inflammation and compromised tissue repair by reduction in cellular and vascular turnover. The more severe periodontal breakdown was caused by 5-FU.

GPR34-mediated sensing of lysophosphatidylserine released by apoptotic neutrophils activates type 3 innate lymphoid cells to mediate tissue repair

Neutrophils migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis. Here we investigated the mechanisms whereby neutrophils participate in tissue repair. In an intestinal epithelia injury model, neutrophil depletion exacerbated colitis and associated with reduced interleukin (IL)-22 and limited activation of type 3 innate lymphoid cells (ILC3s). Co-culture with neutrophils activated ILC3s in a manner dependent on neutrophil apoptosis. Metabolomic analyses revealed that lysophosphatidylserine (LysoPS) from apoptotic neutrophils directly stimulated ILC3 activation. ILC3-specific deletion of Gpr34, encoding the LysoPS receptor GPR34, or inhibition of downstream PI3K-AKT or ERK suppressed IL-22 production in response to apoptotic neutrophils. Gpr34-/- mice exhibited compromised ILC3 activation and tissue repair during colon injury, and neutrophil depletion abrogated these defects. GPR34 deficiency in ILC3s limited IL-22 production and tissue repair invivo in settings of colon and skin injury. Thus, GPR34 is an ILC3-expressed damage-sensing receptor that triggers tissue repair upon recognition of dying neutrophils.

Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype.

Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals. Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner. It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli. Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype. Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span. Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells. It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence. Several other pathways have recently been implicated in mediating senescence and the senescent phenotype. Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.

Surgical OFF-LOADING of the diabetic foot

Diabetic foot ulcer treatment is a challenge for the healthcare world. Widespread infection and the presence of critical ischemia (especially with end-stage renal disease) can lead to major amputation rather than amenable to conservative treatment. Surgical strategies of the diabetic foot have been changing over the past 10 years and are now focused on reconstructive treatment and limb salvage. These goals were achieved, thanks to an evolution of distal revascularization techniques and a distinct approach, which integrates various methods focused on limb salvage. Podoplastic techniques of the diabetic foot are focused on infection clearance, the surgical treatment of corrective deformities, soft tissue coverage and limb ischemia correction along with the management of diabetes and the comorbidities that compromise tissue repair processes. The reconstructive techniques used in diabetic foot treatment owe their effectiveness in part to the results of technological improvements such as the circular external fixator as a tool for stabilization and surgical site protection. In the last decade, many studies have shown that circular external fixation should be considered as the most useful method to protect the reconstructive surgical site in limb salvage of the diabetic foot. The objective of this review is to highlight the role of surgical offloading using circular external fixation as an adjunct to the podoplastic diabetic foot reconstruction procedures.

A model for studying cutaneous wound healing and resilience to aging: Ear punch biopsy in old mice.

Resilience to aging is a biological event that precedes age-related decline in physiological function and is defined as an organism's ability to respond to physical stress with increasing age. There is a need to identify factors that may predict resilience for enhancing and maintaining healthy aging. Older people often experience delayed wound healing beause of compromised tissue repair and immune response. Therefore preclincal models may be of value to investigate the relationship between cutaneous wound healing and resilience to aging. This brief report descibes an ear punch biopsy model of cutaneous wound healing in aging mice and shows that mice with biopsy ear wounds that heal more quickly have better cognition, increased strength and better running endurance later in life.

Topical Application of Recombinant Human MG53 Protein Facilitates Healing of Chronic Wounds in Diabetic Mice

Wound care is a major challenge to public health and the burden for wound treatment is growing due to the aging population and the sharp rise in the incidence of diabetes and obesity, diseases that contribute to poor wound healing. While multiple factors may contribute to complications associated with wound healing, compromised tissue repair represents an underlying cause for non‐healing wounds in diabetes. We previously identified a novel TRIM family protein, named MG53, as an essential component of the cell membrane repair machinery. Here we tested the therapeutic value of using recombinant human MG53 (rhMG53) protein to treat chronic wounds. We developed a prototype formulation of rhMG53 in a topical cream that remains stable for long‐term storage at 4°C and is suitable for wound healing applications. We developed a mouse model of chronic excisional dermal wound using the db/db mice. Under control conditions, dermal wounds in the db/db mice would not heal until day 21. Treatment with topical cream containing 1.5 and 10 mg/oz of rhMG53 accelerated wound healing. Application of the topical cream without rhMG53 was ineffective. Wounds treated with 10 mg/oz rhMG53 cream healed nearly completely by day 12. Histological analyses revealed remarkable improvement of hair follicle structure at the dermal wound site in db/db mice that received treatment with rhMG53; the healing site that received cream alone showed defective hair follicles. We have previously demonstrated that genetic ablation of MG53 led to defective hair follicle structure in the mg53−/− mice. Our findings suggest that MG53 could improve chronic wound healing in diabetes by enhancing the hair follicle structure and the regenerative capacity of the skin.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Zinc Binding to MG53 Facilitates Repair of Injury to Cell Membrane

Zinc (Zn) is an essential trace element that participates in a wide range of biological functions, including wound healing. While Zn deficiency has been linked to compromised wound healing and tissue repair in human diseases, the molecular mechanisms underlying Zn-mediated tissue repair remain unknown. Our previous studies established that MG53, a tripartite motif (TRIM) family protein, is an essential component of the cell membrane repair machinery. Domain homology analysis reveals that MG53 contains two Zn-binding motifs. Here we show that Zn-binding to MG53 is indispensible to the assembly of the cell membrane repair machinery. Live cell imaging illustrates that Zn entry from extracellular space is essential for translocation of MG53-containing vesicles to the acute membrane injury sites for formation of a repair patch. The effect of Zn on membrane repair is abolished in the mg53-/- muscle fibers, suggesting that MG53 functions as a potential target for Zn during membrane repair. Mutagenesis studies suggest that both RING and B-box motifs of MG53 constitute Zn-binding domains that contribute to MG53-mediated membrane repair. Overall, this study establishes a base for Zn interaction with MG53 in protection against injury to the cell membrane.

Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjögren's Syndrome.

Chronic inflammation of the lacrimal gland results in changes in the composition of the extracellular matrix (ECM), which is believed to compromise tissue repair. We hypothesized that increased production/activity of matrix metalloproteinases (MMPs), especially MMP-2 and -9, in inflamed lacrimal glands modifies the ECM environment, therefore disrupting tissue repair. The lacrimal glands from female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for histology, immunohistochemistry, zymography, Western blotting, and RNA analyses. In another study, MRL/lpr mice were treated for 5 weeks with a selective MMP2/9 inhibitor peptide or a control peptide. At the end of treatment, the lacrimal glands were excised and the tissue was processed as described above. There was a 2.5- and 2.7-fold increase in MMP2 gene expression levels in MRL/lpr and NOD mice, respectively. Matrix metalloproteinase 2 and 9 enzymatic activities and protein expression levels were significantly upregulated in the lacrimal glands of MRL/lpr and NOD mice compared to controls. Treatment with the MMP2/9 inhibitor resulted in decreased activity of MMP-2 and -9 both in vitro and in vivo. Importantly, MMP2/9 inhibitor treatment of MRL/lpr mice improved aqueous tear production and resulted in reduced number and size of lymphocytic foci in diseased lacrimal glands. We conclude that MMP2/9 expression and activity are elevated in lacrimal glands of two murine models of Sjögren's syndrome, suggesting that manipulation of MMP2/9 activity might be a potential therapeutic target in chronically inflamed lacrimal glands.

Zinc Binding to MG53 Protein Facilitates Repair of Injury to Cell Membranes

Zinc is an essential trace element that participates in a wide range of biological functions, including wound healing. Although Zn(2+) deficiency has been linked to compromised wound healing and tissue repair in human diseases, the molecular mechanisms underlying Zn(2+)-mediated tissue repair remain unknown. Our previous studies established that MG53, a TRIM (tripartite motif) family protein, is an essential component of the cell membrane repair machinery. Domain homology analysis revealed that MG53 contains two Zn(2+)-binding motifs. Here, we show that Zn(2+) binding to MG53 is indispensable to assembly of the cell membrane repair machinery. Live cell imaging illustrated that Zn(2+) entry from extracellular space is essential for translocation of MG53-containing vesicles to the acute membrane injury sites for formation of a repair patch. The effect of Zn(2+) on membrane repair is abolished in mg53(-/-) muscle fibers, suggesting that MG53 functions as a potential target for Zn(2+) during membrane repair. Mutagenesis studies suggested that both RING and B-box motifs of MG53 constitute Zn(2+)-binding domains that contribute to MG53-mediated membrane repair. Overall, this study establishes a base for Zn(2+) interaction with MG53 in protection against injury to the cell membrane.

Up-regulation of Thrombospondin-2 in Akt1-null Mice Contributes to Compromised Tissue Repair Due to Abnormalities in Fibroblast Function

Vascular remodeling is essential for tissue repair and is regulated by multiple factors, including thrombospondin-2 (TSP2) and hypoxia/VEGF-induced activation of Akt. In contrast to TSP2 knock-out (KO) mice, Akt1 KO mice have elevated TSP2 expression and delayed tissue repair. To investigate the contribution of increased TSP2 to Akt1 KO mice phenotypes, we generated Akt1/TSP2 double KO (DKO) mice. Full-thickness excisional wounds in DKO mice healed at an accelerated rate when compared with Akt1 KO mice. Isolated dermal Akt1 KO fibroblasts expressed increased TSP2 and displayed altered morphology and defects in migration and adhesion. These defects were rescued in DKO fibroblasts or after TSP2 knockdown. Conversely, the addition of exogenous TSP2 to WT cells induced cell morphology and migration rates that were similar to those of Akt1 KO cells. Akt1 KO fibroblasts displayed reduced adhesion to fibronectin with manganese stimulation when compared with WT and DKO cells, revealing an Akt1-dependent role for TSP2 in regulating integrin-mediated adhesions; however, this effect was not due to changes in β1 integrin surface expression or activation. Consistent with these results, Akt1 KO fibroblasts displayed reduced Rac1 activation that was dependent upon expression of TSP2 and could be rescued by a constitutively active Rac mutant. Our observations show that repression of TSP2 expression is a critical aspect of Akt1 function in tissue repair.

Strategies to direct the enrichment, expansion, and recruitment of regulatory cells for the treatment of disease.

Disease and injury perturb the balance of processes associated with inflammation and tissue remodeling, resulting in positive feedback loops, exacerbation of disease and compromised tissue repair. Conversely, under homeostatic healthy conditions, these processes are tightly regulated through the expansion and/or recruitment of specific cell populations, promoting a balanced steady-state. Better understanding of these regulatory processes and recent advances in biomaterials and biotechnology have prompted strategies to utilize cells for the treatment and prevention of disease through regulation of inflammation and promotion of tissue repair. Herein, we describe how cells that regulate these processes can be increased in prevalence at a site of disease or injury. We review several relevant cell therapy approaches as well as new strategies for directing endogenous regulatory cells capable of promoting environmental homeostasis and even the establishment of a pro-regenerative micro-environment. Collectively, these examples may provide a blueprint for next-generation "medicine" that spurs the body's own cells to action and replaces conventional drugs.

S-13 : Interleukin-6 drives tissue fibrosis in response to repeat acute inflammation

Aims: Appropriate control of acute inflammation in response to bacterial infection ensures competent host defense, whilst limiting adverse inflammation-induced injury. Recurrent bouts of infection however drive tissue damage or fibrosis. Studies examined the mechanisms that underpin these differences in inflammatory outcome. Methods: Studies examined the cellular events that dictate transition of an acute resolving inflammatory response into a more damaging inflammatory setting. Peritonitis provides an excellent opportunity to evaluate this process, since recurrent infections in renal failure patients on peritoneal dialysis is a major reason for treatment failure. Here, the frequency or severity of peritonitis correlates with increased tissue fibrosis, vascular damage and retention of activated leukocytes in the peritoneal cavity. We therefore developed a novel murine model of peritoneal inflammation, which promotes peritoneal fibrosis following repeated challenge with a microbial-derived stimulus (SES). This approach allowed us to track temporal changes in the inflammation that affect peritoneal cytokine production, leukocyte recruitment and activation, and the response of the resident stromal tissue. Results: Fibrosis was strictly interleukin (IL)-6 dependent. Repeat inflammation induced IL-6-mediated T-helper 1 (Th1) cell effector commitment and the emergence of STAT1 (Signal Transducer and Activator of Transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon (IFN)-g, STAT1 or RAG-1. Here, IFN-g and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6 deficient mice resisted fibrosis, transfer of polarised Th1 cells or inhibition of MMP activity reversed this outcome. Conclusions: Interleukin-6 causes compromised tissue repair by shifting acute inflammation into a more chronic pro-fibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation. Here, recurrent innate inflammatory activation inadvertently promote adaptive immune responses that alter the pattern of cytokine signaling in stromal tissue, which ultimately gives rise to fibrosis and chronicity.

Interleukin-6 Signaling Drives Fibrosis in Unresolved Inflammation

SummaryFibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.

Friend or foe: emerging role of nuclear factor kappa-light-chain-enhancer of activated B cells in cell senescence.

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) proteins are a family of ubiquitously expressed transcription factors that regulate the response to cellular stress. They mediate innate and adaptive immunity through the initiation of an inflammatory response to pro-inflammatory signals. The role of persistent inflammation in aiding tumor development has led to the NF-κB family of transcription factors being strongly implicated in promoting cancer. However, recent studies have now revealed that NF-κB can also function as a tumor suppressor through the induction of cellular senescence. Cellular senescence is a stable cell cycle arrest that normal cells undergo in response to a variety of intrinsic and extrinsic stimuli including: progressive telomere shortening, changes in telomeric structure, or other forms of genotoxic stress. Senescence can compromise tissue repair and regeneration, contributing to tissue and organismal aging via the accumulation of senescent cells, depletion of stem/progenitor cells and secretion of an array of inflammatory cytokines, chemokines, and matrix metalloproteinases. Senescence can also lead to the removal of potentially cancerous cells, thereby acting as a potent tumor suppressor mechanism. Herein, we review the evidence indicating a role for NF-κB in tumor suppression via cellular senescence and suggest that depending upon the subunit expressed, the biological context, and the type and intensity of the signal, NF-κB can indeed promote senescence growth arrest.

79 : IL-6 regulation of Th1 responses drives fibrosis in unresolved inflammation

Fibrosis in response to periodic infection is a complication of renal failure patients on peritoneal dialysis and suggests a failure to appropriately resolve inflammation. To mimic this situation a model of inflammation-induced peritoneal fibrosis was created by repeatedly challenging mice with a cell-free extract from Staphylococcus epidermidis (SES). Here, fibrosis was strictly interleukin (IL)-6 dependent, and showed no involvement of classical pro-fibrotic cytokines such as IL-4, IL-13 and SMAD3 signaling by TGF β . Instead, recurrent inflammation drove the IL-6-mediated expansion of interferon (IFN)- γ -secreting CD4 + Th1 cells, which promoted an emergence of STAT1 (Signal Transducer and Activator of Transcription-1) activity within the peritoneal membrane of repeatedly challenged mice. Increases in STAT1 activity were only seen in peritoneal membrane of wild type mice and was associated with the induction of STAT1 target genes (IRF-1, ISG-15). Fibrosis and alterations in STAT1 signaling was not observed in mice lacking IL-6, IFN γ , STAT1 or RAG1. Expansion of Th1 cells from naive T-cells required CD126 (IL6R) signaling and conditioned media from SES challenged resident peritoneal monocytic cells selectively promoted IFN γ , but not IL-4, IL-9, IL-13 or IL-17A, secreting CD4 + Tcells. SES did not however promote the innate production of IFN γ by CD19 + B-cells. While IL-6 deficient mice resisted fibrosis, transfer of SES polarized Th1 cells or inhibition of MMP activity through inclusion of RO32-355 (a broad spectrum MMP inhibitor) in drinking water reversed this outcome. Here, IFN γ /STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases (MMP-1, MMP-2, MMP-3, MMP-9). Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic pro-fibrotic state through induction of Th1 responses as a consequence of recurrent inflammation.

CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury

Macrophage G2A and CD36 lipid receptors are thought to mediate efferocytosis following tissue injury and thereby prevent excessive inflammation that could compromise tissue repair. To test this, we subjected mice lacking G2A or CD36 receptor to bleomycin-induced lung injury and measured efferocytosis, inflammation, and fibrosis. Loss of CD36 (but not G2A) delayed clearance of apoptotic alveolar cells (mean 78% increase in apoptotic cells 7 days postinjury), potentiated inflammation (mean 56% increase in lung neutrophils and 75% increase in lung KC levels 7 days postinjury, 51% increase in lung macrophages 14 days postinjury), and reduced lung fibrosis (mean 41% and 29% reduction 14 and 21 days postinjury, respectively). Reduced fibrosis in CD36(-/-) mice was associated with lower levels of profibrotic TH2 cytokines (IL-9, IL-13, IL-4), decreased expression of the M2 macrophage marker Arginase-1, and reduced interstitial myofibroblasts. G2A, on the other hand, was required for optimal clearance of apoptotic neutrophils during zymosan-induced peritoneal inflammation (50.3% increase in apoptotic neutrophils and 30.6% increase in total neutrophils 24 h following zymosan administration in G2A(-/-) mice). Thus, CD36 is required for timely removal of apoptotic cells in the context of lung injury and modulates subsequent inflammatory and fibrotic processes relevant to fibrotic lung disease.