Biomedical subjects

David A Zisman

Publications and source records attributed to David A Zisman.

13 recordsLinked to original sources

PubMed2007

IL-13 is pivotal in the fibro-obliterative process of bronchiolitis obliterans syndrome.

Acute allograft rejection is considered to be a predominately type 1 immune mediated response to the donor alloantigen. However, the type 2 immune mediated response has been implicated in multiple fibroproliferative diseases. Based on the fibro-obliterative lesion found during bronchiolitis obliterans syndrome (BOS), we hypothesized that the type 2 immune mediated response is involved in chronic lung allograft rejection. Specifically, whereas acute rejection is, in part, a type 1 immune response, chronic rejection is, in part, a type 2 immune response. We found the type 2 cytokine, IL-13, to be elevated and biologically active in human bronchoalveolar lavage fluid during BOS. Translational studies using a murine model of BOS demonstrated increased expression of IL-13 and its receptors that paralleled fibro-obliteration. In addition, in vivo neutralization of IL-13 reduced airway allograft matrix deposition and murine BOS, by a mechanism that was independent of IL-4. Furthermore, using IL-13Ralpha2(-/-) mice, we found increased fibro-obliteration. Moreover, anti-IL-13 therapy in combination with cyclosporin A had profound effects on reducing murine BOS. This supports the notion that IL-13 biological axis plays an important role during the pathogenesis of BOS independent of the IL-4 biological axis.

Animals↗

PubMed2006

Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease.

Fibrotic interstitial lung diseases are illnesses of unknown cause characterized by progressive decline in lung function. Fibrocytes are bone marrow-derived, circulating progenitor cells capable of differentiating into diverse mesenchymal cell types. Prior work has shown fibrocytes to traffic to the lung via the CXCL12-CXCR4 chemokine axis in an animal model of pulmonary fibrosis. We therefore assessed the relevance of fibrocytes in patients with fibrotic interstitial lung disease. We found enhanced expression of CXCL12 in both the lungs and plasma of patients with lung fibrosis. CXCL12 levels were associated with an order of magnitude higher number of circulating fibrocytes in the peripheral blood of these patients. Most of the circulating fibrocytes in patients with interstitial lung diseases were negative for the myofibroblast marker alpha-smooth muscle actin, suggesting a relatively undifferentiated phenotype. Taken together, these data suggest that fibrocytes are involved in the pathogenesis of human lung fibrosis.

Blood Cells↗

PubMed2006

Usual interstitial pneumonia.

Usual interstitial pneumonia (UIP) is a distinct histological lesion observed in idiopathic pulmonary fibrosis (IPF) but can be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high-resolution thin-section computed tomographic (CT) scans (provided the radiographic features are classical). Historically, patients labeled as "IPF" encompassed a group of disorders, including UIP as well as other idiopathic interstitial pneumonias that differ from UIP in prognosis and responsiveness to therapy. Current recommendations from international consensus statements restrict the term IPF to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of UIP have not been elucidated, but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of UIP is poor. Mean survival following diagnosis approximates 3 years. Current therapies are of unproven value. Corticosteroids or immunosuppressive agents have been most often used, but data affirming benefit are lacking. Lung transplantation is a viable option for patients failing medical therapy. This review discusses diagnostic criteria for UIP (both histopathological and radiographic), natural history and clinical course, and therapeutic approaches (both current and future).

Biomarkers↗

PubMed2006

Transbronchial biopsy in usual interstitial pneumonia.

BACKGROUND: Usual interstitial pneumonia (UIP) is a slowly progressive, usually fatal form of idiopathic interstitial pneumonia for which there is no effective treatment. Transbronchial biopsy (TBB) has been utilized only to exclude other diseases such as sarcoidosis, lymphangitic carcinoma, and infection, for example, but TBB is generally considered to have little role in confirming UIP. OBJECTIVE: To determine whether diagnostic changes of UIP can be appreciated on TBB specimens. DESIGN: Retrospective analysis of TBB specimens from patients with proven UIP. SETTING: Two study sites in the United States. PARTICIPANTS: Twenty-one patients with UIP confirmed by surgical lung biopsy and/or lung explant, and 1 patient with UIP confirmed by clinical and radiographic findings along with follow-up information. MEASUREMENTS AND RESULTS: Adequate tissue for diagnosis was available in 18 cases; in 7 cases (32% overall), there were varying combinations of interstitial fibrosis in a patchwork pattern along with fibroblast foci and/or honeycomb change. These features were considered diagnostic of UIP. Interstitial fibrosis along with fibroblast foci or honeycomb change were seen in two other cases, but the fibrosis lacked a patchwork pattern, and these features were considered consistent with UIP. Nonspecific interstitial fibrosis alone was found in nine cases. CONCLUSIONS: In summary, characteristic histologic features of UIP can be identified on TBB specimens more often than previously appreciated. TBB may be more useful in confirming UIP than previously recognized.

Adult↗

PubMed2005

Pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease limited to the lungs and associated with the histologic appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy. The estimated prevalence in the United States is between 35,000 and 55,000 cases,and evidence suggests that the prevalence is increasing for IPF. Risk factors associated with pulmonary fibrosis include smoking, environmental exposures, gastroesophageal reflux dis-ease, commonly prescribed drugs, diabetes mellitus, infectious agents, and genetic factors. The diagnosis requires a careful history and physical examination, characteristic physiological and radiological studies, and, in some cases, a surgical lung biopsy. The natural history of IPF is not known, but evidence supports the concept of a continuum of idiopathic interstitial pneumonias that may overlap in time. Most patients with IPF succumb to respiratory failure, cardiovascular disease, lung cancer, pulmonary embolism, infection, and other health problems. The median survival time for patients with IPF is less than 3 yr. Factors that predict poor outcome include older age, male gender, severe dyspnea, history of cigarette smoking, severe loss of lung function, appearance and severity of fibrosis on radiological studies, lack of response to therapy,and prominent fibroblastic foci on histopathologic evaluation. Conventional therapy (corticosteroids, azathioprine, cyclophosphamide) provides only marginal benefit. Lung transplantation should be considered for patients with IPF refractory to medical therapy. In light of the poor prognosis and lack of response to available anti-inflammatory therapy, alternative approaches to therapy are being pursued. Emerging strategies to treat patients with IPF include agents that inhibit epithelial injury or enhance repair, anti-cytokine approaches, agents that inhibit fibroblast proliferation or induce fibroblast apoptosis, and other novel approaches.

Adult↗

PubMed2004

CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling.

Aberrant vascular remodeling is a central hallmark for the development and progression of idiopathic pulmonary fibrosis. The mechanisms underlying the pathophysiologic alterations, however, are poorly understood. A recent phase II trial of interferon gamma-1b has demonstrated a trend toward a decrease in profibrotic and proangiogenic biologic markers, and upregulation of lung CXCL11 mRNA and bronchoalveolar lavage fluid and plasma protein levels of CXCL11. We hypothesized that net aberrant vascular remodeling seen during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-induced pulmonary fibrosis can be attenuated by treatment with the angiostatic ELR(-) CXC chemokine, CXCL11. In a preclinical model, systemic administration of CXCL11 reduced pulmonary collagen deposition, procollagen gene expression, and histopathologic fibroplasia and extracellular matrix deposition in the lung of bleomycin-treated mice. CXCL11 treatment significantly reduced bleomycin-induced pulmonary fibrosis without altering specific lung leukocyte populations. CXCR3 is not expressed on fibroblasts and CXCL11 had no direct functional effect on pulmonary fibroblasts. The angiogenic activity in the lung was significantly decreased, however, and CXCL11 treatment reduced the total number of endothelial cells in the lung following bleomycin exposure. The results suggest that CXCL11 inhibits pulmonary fibrosis by altering aberrant vascular remodeling.

Angiogenesis Inhibitors↗

PubMed2004

Association between pulmonary fibrosis and coronary artery disease.

BACKGROUND: Pulmonary fibrosis and atherosclerosis have many similarities at the histopathologic level. Moreover, fibrotic lung diseases exhibit systemic effects and have the potential to affect the vasculature beyond the lung. The existence of a relationship between the two, however, has not been studied. METHODS: To investigate whether fibrotic lung disorders may predispose to atherosclerosis, we conducted a cross-sectional study of 630 patients referred for lung transplantation evaluation at a university hospital. We compared the prevalence of angiographic coronary artery disease (CAD) in patients with fibrotic vs nonfibrotic lung diseases. RESULTS: Fibrotic lung diseases were associated with an increased prevalence of CAD compared with nonfibrotic diseases after adjustment for traditional risk factors (odds ratio, 2.18; 95% confidence interval, 1.17-4.06). The magnitude and significance of this association were maintained when only nongranulomatous fibrotic disease or its subset, idiopathic pulmonary fibrosis, was examined. The strength of the relationship between fibrotic disorders and CAD increased when multivessel disease was analyzed (odds ratio, 4.16; 95% confidence interval, 1.46-11.9). No significant association was detected for granulomatous fibrotic disorders (odds ratio, 1.56; 95% confidence interval, 0.47-5.16; P =.47), although this subgroup had fewer cases of CAD for analysis. CONCLUSIONS: These findings support an association between fibrotic lung disorders and CAD. Further research is necessary to confirm this relationship and to explore the pathologic processes underlying, and potentially linking, these 2 conditions.

Adult↗

PubMed2004

Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches.

Idiopathic pulmonary fibrosis (IPF), also termed cryptogenic fibrosing alveolitis, is a clinicopathological syndrome characterised by cough, exertional dyspneoa, basilar crackles, a restrictive defect on pulmonary function tests, honeycombing on high-resolution, thin-section computed tomographic scans and the histological diagnosis of usual interstitial pneumonia on lung biopsy. The course is usually indolent but inexorable. Most patients die of progressive respiratory failure within 3-8 years of the onset of symptoms. Current therapies are of unproven benefit. Although the pathogenesis of IPF has not been elucidated, early concepts focused on lung injury leading to a cycle of chronic alveolar inflammation eventuating in fibrosis and destruction of the lung architecture. Anti-inflammatory therapies employing corticosteroids or immunosuppressive or cytotoxic agents have been disappointing. More recent hypotheses acknowledge that sequential alveolar epithelial cell injury is likely to be a key event in the pathogenesis of IPF, but the cardinal event is an aberrant host response to wound healing. In this context, abnormal epithelial-mesenchymal interactions, altered fibroblast phenotypes, exaggerated fibroblast proliferation, and excessive deposition of collagen and extracellular matrix are pivotal to the fibrotic process. Several clinical trials are currently underway or in the planning stages, and include drugs such as interferon-gamma 1b, pirfenidone, acetylcysteine, etanercept (a tumor necrosis factor-alpha antagonist), bosentan (an endothelin-1 receptor antagonist) and zileuton (a 5-lypoxygenase inhibitor). Future therapeutic strategies should be focused on alveolar epithelial cells aimed at enhancing re-epithelialisation and on fibroblastic/myofibroblastic foci, which play an essential role in the development of IPF. Stem cell progenitors of the alveolar epithelial cells and genetic and epigenetic therapies are attractive future approaches for this and other fibrotic lung disorders.

Clinical Trials as Topic↗

PubMed2003

Role of CXCL9/CXCR3 chemokine biology during pathogenesis of acute lung allograft rejection.

Acute allograft rejection is a major complication postlung transplantation and is the main risk factor for the development of bronchiolitis obliterans syndrome. Acute rejection is characterized by intragraft infiltration of activated mononuclear cells. The ELR-negative CXC chemokines CXCL9, CXCL10, and CXCL11) are potent chemoattractants for mononuclear cells and act through their shared receptor, CXCR3. Elevated levels of these chemokines in bronchoalveolar lavage fluid have been associated with human acute lung allograft rejection. This led to the hypothesis that the expression of these chemokines during an allogeneic response promotes the recruitment of mononuclear cells, leading to acute lung allograft rejection. We performed studies in a rat orthotopic lung transplantation model of acute rejection, and demonstrated increased expression of CXCL9 and CXCL10 paralleling the recruitment of mononuclear cells and cells expressing CXCR3 to the allograft. However, CXCL9 levels were 15-fold greater than CXCL10 during maximal rejection. Inhibition of CXCL9 decreased intragraft recruitment of mononuclear cells and cellular expression of CXCR3, resulting in lower acute lung allograft rejection scores. Furthermore, the combination of low dose cyclosporin A with anti-CXCL9 therapy had more profound effects on intragraft leukocyte infiltration and in reducing acute allograft rejection scores. This supports the notion that CXCL9 interaction with cells expressing CXCR3 has an important role in the recruitment of mononuclear cells, a pivotal event in the pathogenesis of acute lung allograft rejection.

Acute Disease↗

PubMed2002

Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease.

Doppler echocardiography is commonly used to estimate systolic pulmonary artery pressure and to diagnose pulmonary hypertension, but data relating to its utility in patients with advanced lung disease are limited. In a cohort study of 374 lung transplant candidates, the performance characteristics of echocardiography compared with right heart catheterization in the determination of systolic pulmonary artery pressure and diagnosis of pulmonary hypertension were investigated. The prevalence of pulmonary hypertension was 25% in the study population. Estimation of systolic pulmonary artery pressure by echocardiography was possible in 166 patients (44%). The correlation between systolic pulmonary artery pressure estimated by echocardiography and measured by cardiac catheterization was good (r = 0.69, p < 0.0001). However, 52% of pressure estimations were found to be inaccurate (more than 10 mm Hg difference compared with measured pressure), and 48% of patients were misclassified as having pulmonary hypertension by echocardiography. Sensitivity, specificity, and positive and negative predictive values of systolic pulmonary artery pressure estimation for diagnosis of pulmonary hypertension were 85%, 55%, 52%, and 87%, respectively. In conclusion, despite a statistically significant correlation with directly measured values, estimation of systolic pulmonary artery pressure by echocardiography is frequently inaccurate in patients with advanced lung disease and leads to considerable overdiagnosis of pulmonary hypertension.

Adult↗

PubMed2002

Sarcoidosis involving the musculoskeletal system.

Although sarcoidosis can affect virtually any organ, musculoskeletal involvement is infrequent. Early in the course of the disease, acute polyarthritis may be observed in up to 40% of patients, but this is often self-limited. Chronic or recurrent sarcoid arthritis is rare, affecting only 1 to 4% of patients. Asymptomatic involvement of muscles has been reported in 25 to 75% of patients in small series, but symptomatic involvement of muscles is rare. Although prospective studies assessing the prevalence of muscle involvement in sarcoidosis have not been done, several large retrospective studies suggest that symptomatic muscle involvement occurs in < 0.5% of patients with sarcoidosis. Patterns of sarcoid muscle involvement include chronic, progressive myopathy; nodular or tumorous sarcoidosis affecting muscles; and an acute polymyositis-like syndrome. Corticosteroid therapy is usually efficacious for the acute myositis variant but is less consistently helpful in the other forms (e.g., chronic myopathy or nodules). Similarly, clinically significant involvement of bone is rare (< 2-5%), and is often associated with chronic multisystemic disease, lupus pernio, and chronic uveitis. Unfortunately, osseous sarcoidosis is often unresponsive to therapy. In this review, we discuss the prevalence, clinical features, and management of sarcoidosis involving muscle, joints, and bones.

Journal Article↗

PubMed2002

Cardiopulmonary bypass for bilateral sequential lung transplantation in patients with chronic obstructive pulmonary disease without adverse effect on lung function or clinical outcome.

OBJECTIVE: The use of cardiopulmonary bypass in lung transplantation remains controversial. Previous studies have concluded that cardiopulmonary bypass is deleterious, but these studies were confounded by the inclusion of patients with different diagnoses undergoing single- and double-lung transplantation with elective or emergency use of bypass. The goal of this study was to determine whether cardiopulmonary bypass has deleterious effects on lung function or clinical outcome by analyzing the cases of patients with a single disease entity and elective use of bypass for bilateral sequential lung transplantation. METHODS: A retrospective review of 50 patients with chronic obstructive pulmonary disease who underwent bilateral sequential lung transplantation was performed. Fourteen patients who underwent elective cardiopulmonary bypass for 218.3 +/- 75.4 minutes were compared to 36 control patients. RESULTS: After the operation, the bypass and nonbypass groups were not significantly different with respect to median duration of mechanical ventilation (1 day vs 1 day, P =.76), median stay in the intensive care unit (4 days vs 4 days, P =.44), median hospital stay (15.5 days vs 16 days, P =.74), mean increase in serum creatinine level (1.4 +/- 1.9 mg/dL vs 0.9 +/- 1.0 mg/dL, P =.33), and mean ratio of Pao(2) to fraction of inspired oxygen at 1 hour (376.6 +/- 123 vs 357.0 +/- 218, P =.75), at 24 hours (309.9 +/- 92 vs 350.6 +/- 122, P =.26), and at 48 hours (335.0 +/- 144 vs 316.2 +/- 120, P =.64). Late outcome markers compared between the bypass and nonbypass groups were the following: 1-year percentage predicted forced expiratory volume in 1 second (76.1% +/- 17.0% vs 85.3% +/- 21.7%, P =.24), 30-day mortality (7.1% vs 8.3%, P >.999), 1-year survival (85.7% vs 80.1%, P =.66), 3-year survival (64.3% vs 58.3%, P =.70), and the prevalence of bronchiolitis obliterans syndrome (0% vs 36.1%, P =.01). CONCLUSION: Cardiopulmonary bypass appears to have no deleterious effect on early lung function or clinical outcome. We hope that this pilot study removes some of the unwarranted fear of the use of bypass in lung transplantation for chronic obstructive pulmonary disease.

Analysis of Variance↗

PubMed2002

Usual interstitial pneumonia: histologic study of biopsy and explant specimens.

The pathologic findings in biopsy and subsequent explant specimens from 20 patients with usual interstitial pneumonia (UIP) were reviewed to refine histologic criteria for diagnosis, to identify factors that may confound diagnosis, and to assess the relationship of UIP and nonspecific interstitial pneumonia (NSIP). One case of NSIP was also identified and included for comparison. Surgical biopsies from 15 of the 20 UIP cases were diagnosed as UIP, whereas 5 showed only nondiagnostic changes. An important new observation is that areas resembling nonspecific interstitial pneumonia (NSIP-like areas) are present in the majority of UIP cases in both biopsy and explant specimens, and they are extensive in some. Ten of the 15 UIP biopsies were considered straightforward, with typical patchy interstitial fibrosis, honeycomb change, and fibroblast foci. Five cases were considered difficult because of prominent NSIP-like areas in two, extensive honeycomb change in one, superimposed diffuse alveolar damage in one, and superimposed bronchiolitis obliterans-organizing pneumonia in one. The most helpful feature for diagnosing UIP in difficult cases was the presence of a distinct patchwork appearance to the characteristic uneven or variegated parenchymal involvement along with evidence of architectural derangement. No explant showing UIP was preceded by biopsy findings of NSIP, and the one NSIP case appeared similar at biopsy and explant. NSIP or NSIP-like areas and UIP may reflect different mechanisms of fibrosis related either to different severity of injury or to different injuries.

Adult↗