Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease.

Rationale: Lung fibroblasts are key mediators of fibrosis resulting in accumulation of excessive interstitial collagen and extracellular matrix, but their origins are not well defined. Objectives: We aimed to elucidate the contribution of lung epithelium-derived fibroblasts via epithelial-mesenchymal transition (EMT) in the intratracheal bleomycin model. Methods: Primary type II alveolar epithelial cells were cultured from Immortomice and exposed to transforming growth factor-b 1 and epidermal growth factor. Cell fate reporter mice that permanently mark cells of lung epithelial lineage with b-galactosidase were developed to study EMT, and bone marrow chimeras expressing green fluorescent protein under the control of the fibroblast-associated S100A4 promoter were generated to examine bone marrow-derived fibroblasts. Mice were given intratracheal bleomycin (0.08 unit). Immunostaining was performed for S100A4, b-galactosidase, green fluorescent protein, and a-smooth muscle actin. Measurements and Main Results: In vitro, primary type II alveolar epithelial cells undergo phenotypic changes of EMT when exposed to transforming growth factor-b 1 and epidermal growth factor with loss of prosurfactant protein C and E-cadherin and gain of S100A4 and type I procollagen. In vivo, using cell fate reporter mice, approximately one-third of S100A4-positive fibroblasts were derived from lung epithelium 2 weeks after bleomycin administration. From bone marrow chimera studies, one-fifth of S100A4-positive fibroblasts were derived from bone marrow at this same time point. Myofibroblasts rarely derived from EMT or bone marrow progenitors. Conclusions: Both EMT and bone marrow progenitors contribute to S100A4-positive fibroblasts in bleomycin-induced lung fibrosis. However, neither origin is a principal contributor to lung myofibroblasts.

Recent evidence suggests that dysfunctional type II alveolar epithelial cells (AECs) contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Based on the hypothesis that disease-causing mutations in surfactant protein C ( SFTPC) provide an important paradigm for studying IPF, we investigated a potential mechanism of AEC dysfunction suggested to result from mutant SFTPC expression: induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We evaluated biopsies from 23 IPF patients (including 3 family members with L188Q SFTPC mutations, 10 individuals with familial interstitial pneumonia without SFTPC mutations, and 10 individuals with sporadic IPF) and sections from 10 control lungs. After demonstrating UPR activation in cultured A549 cells expressing mutant SFTPC, we identified prominent expression of UPR markers in AECs in the lungs of patients with SFTPC mutation-associated fibrosis. In individuals with familial interstitial pneumonia without SFTPC mutations and patients with sporadic IPF, we also found UPR activation selectively in AECs lining areas of fibrotic remodeling. Because herpesviruses are found frequently in IPF lungs and can induce ER stress, we investigated expression of viral proteins in lung biopsies. Herpesvirus protein expression was found in AECs from 15/23 IPF patients and colocalized with UPR markers in AECs from these patients. ER stress and UPR activation are found in the alveolar epithelium in patients with IPF and could contribute to disease progression. Activation of these pathways may result from altered surfactant protein processing or chronic herpesvirus infection.

Interstitial lung fibrosis can develop as a consequence of occupational or medical exposure, as a result of genetic defects, and after trauma or acute lung injury leading to fibroproliferative acute respiratory distress syndrome, or it can develop in an idiopathic manner. The pathogenesis of each form of lung fibrosis remains poorly understood. They each result in a progressive loss of lung function with increasing dyspnea, and most forms ultimately result in mortality. To better understand the pathogenesis of lung fibrotic disorders, multiple animal models have been developed. This review summarizes the common and emerging models of lung fibrosis to highlight their usefulness in understanding the cell-cell and soluble mediator interactions that drive fibrotic responses. Recent advances have allowed for the development of models to study targeted injuries of Type II alveolar epithelial cells, fibroblastic autonomous effects, and targeted genetic defects. Repetitive dosing in some models has more closely mimicked the pathology of human fibrotic lung disease. We also have a much better understanding of the fact that the aged lung has increased susceptibility to fibrosis. Each of the models reviewed in this report offers a powerful tool for studying some aspect of fibrotic lung disease.Keywords: fibrosis; collagen; fibroblast; aging; cytokines Interstitial lung disease is often associated with the development of chronic fibrosis. These diseases are characterized clinically by progressive dyspnea, cough, restrictive physiology, and impaired gas exchange. Humans manifest many types of fibrotic lung disease (1). Among the diffuse parenchymal lung disorders (DPLDs) are diseases of known cause (e.g., drug-related, environmental exposures, or those associated with collagen vascular disease), the idiopathic interstitial pneumonias (IIPs), the granulomatous DPLDs (e.g., sarcoidosis), and rare noncategorized diseases, such as lymphangioleiomyomatosis. Idiopathic pulmonary fibrosis (IPF) is the most common disease within the category of IIPs, and is histopathologically identified as usual interstitial pneumonia (UIP). Additional diseases within the IIP category include desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, acute interstitial pneumonia, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia, and nonspecific interstitial pneumonia (NSIP). IPF carries a poor prognosis, with a mean survival time of less than 5 years after diagnosis (2-5). Biopsies from a single patient can show heterogenous patterns consistent with both UIP and NSIP (4, 6, 7), suggesting that NSIP shares common pathogenic mechanisms with UIP.Diagnoses of patients with IPF who do not exhibit classic high-resolution computed tomography scan changes are confirmed by histopathologic evaluations of surgical lung biopsies, which demonstrate the pattern of UIP. Hallmark features of UIP include epithelial cell hyperplasia, basement membrane denudation, alveolar consolidation, and fibroblastic foci in a pa...

The success of the use of vascularized bone free flaps in restoring continuity to the mandible is clearly demonstrated in this series. There was an acceptable incidence of donor- and recipient-site complications that resulted in minimal long-term morbidity. The careful selection of a donor site(s) for oromandibular reconstruction allows for an optimal restoration of bony and soft tissue defects. Dental implants can be safely used in oromandibular reconstruction with a high level of success. Placing these implants during the initial surgery shortens the duration for achieving dental rehabilitation and enhances the success of the implants when postoperative radiotherapy is administered.

Evidence of endoplasmic reticulum (ER) stress has been found in lungs of patients with familial and sporadic idiopathic pulmonary fibrosis. We tested whether ER stress causes or exacerbates lung fibrosis by ( i ) conditional expression of a mutant form of surfactant protein C (L188Q SFTPC ) found in familial interstitial pneumonia and ( ii ) intratracheal treatment with the protein misfolding agent tunicamycin. We developed transgenic mice expressing L188Q SFTPC exclusively in type II alveolar epithelium by using the Tet-On system. Expression of L188Q SFTPC induced ER stress, as determined by increased expression of heavy-chain Ig binding protein (BiP) and splicing of X-box binding protein 1 (XBP1) mRNA, but no lung fibrosis was identified in the absence of a second profibrotic stimulus. After intratracheal bleomycin, L188Q SFTPC -expressing mice developed exaggerated lung fibrosis and reduced static lung compliance compared with controls. Bleomycin-treated L188Q SFTPC mice also demonstrated increased apoptosis of alveolar epithelial cells and greater numbers of fibroblasts in the lungs. With a complementary model, intratracheal tunicamycin treatment failed to induce lung remodeling yet resulted in augmentation of bleomycin-induced fibrosis. These data support the concept that ER stress produces a dysfunctional epithelial cell phenotype that facilitates fibrotic remodeling. ER stress pathways may serve as important therapeutic targets in idiopathic pulmonary fibrosis.

Inverted papilloma is a benign sinonasal tumor which is locally aggressive and has a significant malignant potential. This report updates the experience of the two senior authors, who have treated 112 patients with inverted papilloma at the Mount Sinai Medical Center over a 20-year period. As clinical examination often underestimates tumor extent, preoperative radiographic assessment is of paramount importance in guiding selection of surgical therapy. Complete en bloc excision via lateral rhinotomy and medial maxillectomy was the method of treatment in the majority of patients (84%). In selected patients with limited disease, or in patients who refused en bloc excision, conservative therapy employing intranasal or transantral ethmoidectomy was performed. The recurrence rates for the two groups were 14% and 20%, respectively. Recurrent disease developed throughout the paranasal sinuses, with the maxillary antrum and ethmoid labyrinth constituting the major sites. In two patients presenting with anterior skull base erosion, craniofacial resection was undertaken to eradicate disease. The latter cases underscore the aggressive nature of the tumor if left untreated. The overall rate of squamous carcinoma in this series was 5%. Given the predilection for local recurrence, multicentricity, and the possibility of malignancy, the authors continue to recommend lateral rhinotomy and medial maxillectomy as the standard therapy for the majority of cases. Management principles as well as a review of the literature are discussed.

Single-dose intratracheal bleomycin has been instrumental for understanding fibrotic lung remodeling, but fails to recapitulate several features of idiopathic pulmonary fibrosis (IPF). Since IPF is thought to result from recurrent alveolar injury, we aimed to develop a repetitive bleomycin model that results in lung fibrosis with key characteristics of human disease, including alveolar epithelial cell (AEC) hyperplasia. Wild-type and cell fate reporter mice expressing β-galactosidase in cells of lung epithelial lineage were given intratracheal bleomycin after intubation, and lungs were harvested 2 wk after a single or eighth biweekly dose. Lungs were evaluated for fibrosis and collagen content. Bronchoalveolar lavage (BAL) was performed for cell counts. TUNEL staining and immunohistochemistry were performed for pro-surfactant protein C (pro-SP-C), Clara cell 10 (CC-10), β-galactosidase, S100A4, and α-smooth muscle actin. Lungs from repetitive bleomycin mice had marked fibrosis with prominent AEC hyperplasia, similar to usual interstitial pneumonia (UIP). Compared with single dosing, repetitive bleomycin mice had greater fibrosis by scoring, morphometry, and collagen content; increased TUNEL+ AECs; and reduced inflammatory cells in BAL. Sixty-four percent of pro-SP-C+ cells in areas of fibrosis expressed CC-10 in the repetitive model, suggesting expansion of a bronchoalveolar stem cell-like population. In reporter mice, 50% of S100A4+ lung fibroblasts were derived from epithelial mesenchymal transition compared with 33% in the single-dose model. With repetitive bleomycin, fibrotic remodeling persisted 10 wk after the eighth dose. Repetitive intratracheal bleomycin results in marked lung fibrosis with prominent AEC hyperplasia, features reminiscent of UIP.