The tumor suppressor WW domain-containing oxidoreductase (WWOX) exhibits regulatory interactions with an array of transcription factors and signaling molecules that are positioned at the well-known crossroads between inflammation and cancer. WWOX is also subject to downregulation by genotoxic environmental exposures, making it of potential interest to the study of lung pathobiology. Knockdown of lung WWOX expression in mice was observed to cause neutrophil influx and was accompanied by a corresponding vascular leak and inflammatory cytokine production. In cultured human alveolar epithelial cells, loss of WWOX expression resulted in increased c-Jun- and IL-8-dependent neutrophil chemotaxis toward cell monolayers. WWOX was observed to directly interact with c-Jun in these cells, and its absence resulted in increased nuclear translocation of c-Jun. Finally, inhibition of the c-Jun-activating kinase JNK abrogated the lung neutrophil influx observed during WWOX knockdown in mice. Altogether, these observations represent a novel mechanism of pulmonary neutrophil influx that is highly relevant to the pathobiology and potential treatment of a number of different lung inflammatory conditions.

Idiopathic pulmonary fibrosis is a deadly disease characterized by excessive extracellular matrix deposition in the lungs, resulting in decreased pulmonary function. Although epithelial cells and fibroblasts have long been the focus of idiopathic pulmonary fibrosis research, the role of various subpopulations of macrophages in promoting a fibrotic response is an emerging target. Healthy lungs are composed of two macrophage populations, tissue-resident alveolar macrophages and interstitial macrophages, which help to maintain homeostasis. After injury, tissue-resident alveolar macrophages are depleted, and monocytes from the bone marrow (BM) traffic to the lungs along a CCL2/CCR2 axis and differentiate into monocyte-derived alveolar macrophages (Mo-AMs), which is a cell population implicated in murine models of pulmonary fibrosis. In this study, we sought to determine how IL-1R-associated kinase-M (IRAK-M), a negative regulator of TLR signaling, modulates monocyte trafficking into the lungs in response to bleomycin. Our data indicate that after bleomycin challenge, mice lacking IRAK-M have decreased monocyte trafficking and reduced Mo-AMs in their lungs. Although IRAK-M expression did not regulate differences in chemokines, cytokines, or adhesion molecules associated with monocyte recruitment, IRAK-M was necessary for CCR2 upregulation following bleomycin challenge. This finding prompted us to develop a competitive BM chimera model, which demonstrated that expression of BMderived IRAK-M was necessary for monocyte trafficking into the lung and for subsequent enhanced collagen deposition. These data indicate that IRAK-M regulates monocyte trafficking by increasing the expression of CCR2, resulting in enhanced monocyte translocation into the lung, Mo-AM differentiation, and development of pulmonary fibrosis.

Background Fibula free flaps (FFF) are often considered the first choice for mandibular reconstruction, but scapular system free flaps (SFF) have increased in popularity due to versatility, donor site advantages, and patient factors. Methods Retrospective chart review of patients undergoing mandibulectomy with FFF or SFF reconstruction from 2016 to 2021. Results Hundred and seventy‐six patients (FFF n = 145, SFF n = 31) underwent the aforementioned procedures. Mean FFF operative time was 9.47 h versus 9.88 for SFF (p = 0.40). Two‐flap reconstructions required 12.65 h versus 10.09 for SFF with soft tissue (p = 0.002). Donor site complications were identified in 65.6% of FFF with skin grafting. Conclusions These findings suggest that SFF requires similar operative time and results in reduced donor site morbidity as compared to FFF. Supine, concurrent harvesting of SFF allows for single‐flap harvest with significantly shorter operative time. SFF could be considered a primary option for mandible reconstruction for complex defects and in select patients.

Idiopathic pulmonary fibrosis (IPF) is characterized by increased collagen accumulation that is progressive and non-resolving. Although fibrosis progression may be regulated by fibroblasts and alveolar macrophage (AM) interactions, this cellular interplay has not been fully elucidated. To study AM-fibroblast interactions, cells were isolated from IPF and normal human lung tissue and cultured independently or together in direct 2D co-culture, direct 3D co-culture, indirect transwell, and in 3D hydrogels. AM influence on fibroblast function was assessed by gene expression, cytokine/chemokine secretion, and gel/matrix contractility. Normal AMs cultured in direct contact with fibroblasts down-regulated ECM gene expression while IPF AMs showed little to no effect. Fibroblast contractility was assessed by encapsulating co-cultures in 3D collagen hydrogels and monitoring gel diameter over time. Both normal and IPF AMs reduced baseline contractility of normal fibroblasts but had little to no effect on IPF fibroblasts. When stimulated with Toll-like receptor (TLR) agonists, IPF AMs increased production of pro-inflammatory cytokines TNFα and IL-1β, compared to normal AMs. TLR ligand stimulation did not alter fibroblast contraction, but stimulation with exogenous TNFα and TGF-β did alter contraction. To determine if the observed changes required cell-to-cell contact, AM-conditioned media and transwell systems were utilized. Transwell culture showed decreased ECM gene expression changes compared to direct co-culture and conditioned media from AMs did not alter fibroblast contraction regardless of disease state. Taken together, these data indicate that normal fibroblasts are more responsive to AM crosstalk, and that AM influence on fibroblast behavior depends on cell proximity.

Objectives Osseous microvascular free tissue transfer (MFTT) is the gold standard for reconstruction for most segmental mandibulectomy defects. The most common osseous MFTT utilized in reconstruction is the fibular, scapular, and osteocutaneous radial forearm (OCRF) free flap. We evaluated postoperative bone union as well as clinical complications following MFTT and the impact of various patient and reconstructive characteristics, including type of osseous MFTT. Study Design Retrospective cohort study. Setting Tertiary care academic hospital. Methods This study examined patients who underwent osseous MFTT for mandibular defects from January 2017 to January 2019. Results An overall 144 osteotomies in 58 patients were evaluated. Of the 144 junctions, 28 (19.4%) showed radiographic nonunion. Patients who underwent preoperative (odds ratio [OR] = 0.30, P = .027) and postoperative (OR = 0.28, P = .003) radiation had a significantly lower bone union score. Time from surgery to postoperative imaging was associated with higher bone union scores (OR = 1.07, P = .024). When bone union scores were compared among types of MFTT, fibular (OR = 5.62, P = .008) and scapular (OR = 4.69, P = .043) MFTT had significantly higher scores than OCRF MFTT. Twelve (20.7%) patients had postoperative complications. There was no statistically significant correlation between clinical complications and various variables, including type of osseous MFTT. Conclusion Pre- and postoperative radiation and time from surgery have an impact on bone union. Regarding the type of MFTT, fibular and scapular MFTT appeared to have higher bone union when compared with OCRF. There was no impact of bone union or type of osseous MFTT on clinical complications.