Pulmonary Vaccination as a Novel Treatment for Lung Fibrosis

Pulmonary fibrosis is an untreatable, uniformly fatal disease of unclear etiology that is the result of unremitting chronic inflammation. Recent studies have implicated bone marrow derived fibrocytes and M2 macrophages as playing key roles in propagating fibrosis. While the disease process is characterized by the accumulation of lymphocytes in the lung parenchyma and alveolar space, their role remains unclear. In this report we definitively demonstrate the ability of T cells to regulate lung inflammation leading to fibrosis. Specifically we demonstrate the ability of intranasal vaccinia vaccination to inhibit M2 macrophage generation and fibrocyte recruitment and hence the accumulation of collagen and death due to pulmonary failure. Mechanistically, we demonstrate the ability of lung Th1 cells to prevent fibrosis as vaccinia failed to prevent disease in Rag−/− mice or in mice in which the T cells lacked IFN-γ. Furthermore, vaccination 3 months prior to the initiation of fibrosis was able to mitigate the disease. Our findings clearly demonstrate the role of T cells in regulating pulmonary fibrosis as well as suggest that vaccinia-induced immunotherapy in the lung may prove to be a novel treatment approach to this otherwise fatal disease

Pulmonary Manifestations of Polymyositis/Dermatomyositis

Abstract The idiopathic inflammatory myopathies are a group of connective tissue diseases marked by varying degrees of muscle inflammation and clinical involvement of multiple organs, most notably, the lung. Pulmonary manifestations consist primarily of interstitial lung disease (ILD), which is associated with significant morbidity and mortality in myositis patients. Several myositis-specific antibodies have been discovered, as well as antibodies targeting various aminoacyl-tRNA synthetase enzymes. These antibodies are associated with various clinical features and a risk for developing ILD, and their presence carries a prognostic value in myositis patients. Steroids remain the first-line treatment for myositis-associated ILD and the antisynthetase syndrome, though other traditional immunosuppressants have demonstrated efficacy in numerous studies. While a majority of patients experience either stabilization or improvement in lung imaging and function, fatal progression is still reported in a significant number of cases. Further research is needed to develop more effective and targeted therapies

Severe pulmonary hypertension in idiopathic nonspecific interstitial pneumonia

Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD), particularly in idiopathic pulmonary fibrosis (IPF) and ILD associated with connective tissue disease, where the underlying pathology is often a nonspecific interstitial pneumonia (NSIP) pattern. The degree of PH in ILD is typically mild to moderate and radiographic changes of ILD are usually prominent. We describe four patients with idiopathic NSIP and severe PH (mPAP > 40 mmHg). The average mean pulmonary artery pressure was 51±7 mmHg and pulmonary vascular resistance was 13±4 Wood's units. Pulmonary function was characterized by mild restriction (total lung capacity 63–94% predicted) and profound reductions in DLCO (19–53% predicted). Computed tomographic imaging revealed minimal to moderate interstitial thickening without honeycombing. In two of the cases, an initial clinical diagnosis of idiopathic pulmonary arterial hypertension was made. Both were treated with intravenous epoprostenol, which was associated with worsening of hypoxemia. All four patients died or underwent lung transplant within 4 years of PH diagnonsis. Lung pathology in all four demonstrated fibrotic NSIP with medial thickening of the small and medium pulmonary arteries, and proliferative intimal lesions that stained negative for endothelial markers (CD31 and CD34) and positive for smooth muscle actin. There were no plexiform lesions. Severe pulmonary hypertension can therefore occur in idiopathic NSIP, even in the absence of advanced radiographic changes. Clinicians should suspect underlying ILD as the basis for PH when DLCO is severely reduced or gas exchange deteriorates with pulmonary vasodilator therapy

Vaccinia vaccination abrogates bleomycin induced pulmonary fibrosis.

<p>A. Histological analysis of lungs of vaccinia vaccinated and mock (PBS) vaccinated mice following bleomycin administration. B. Total lung collagen concentration following bleomycin administration. C. Flow cytometry and graphical analysis of fibrocyte (CD45⁺, Collagen⁺) numbers in lungs of mice 7 days after bleomycin administration. Error bars indicate one standard deviation of the mean and (*) indicates statistical significance (p<.05) between groups. All experiments were performed at least three times, at least 10 animals per group per experiment.</p

Vaccinia vaccination provides long term protection against bleomycin induced pulmonary fibrosis.

<p>Survival curves of mice vaccinia vaccinated or mock (PBS) vaccinated either six weeks (A.) eight weeks (B.) or twelve weeks (C.) prior to bleomycin administration. All experiments were performed at least three times, at least 10 animals per group per experiment.</p

Vaccinia vaccinated mice display greater lung T cell numbers and enhanced function following bleomycin challenge.

<p>A. Total lung cell numbers of vaccinia vaccinated and mock (PBS) vaccinated mice following bleomycin administration. B. Total CD4⁺ and CD8⁺ T cells present in the lung following bleomycin administration. C. Flow cytometric analysis of percentages of lung CD4⁺ and CD8⁺ T cells. D. Total lung CD4⁺ IFNγ⁺ and CD8⁺ IFNγ⁺ T cells following bleomycin administration. E. ELISA analysis of IFNγ concentration in bronchial lavage fluid following bleomycin administration. F. Total lung CD4⁺ IL17⁺ T cells following bleomycin administration. Error bars indicate one standard deviation of the mean and (*) indicates statistical significance (p<.05) between groups. All experiments were performed at least three times, at least 10 animals per group per experiment.</p

Vaccinia vaccinated mice have greater numbers of lung M1 macrophages and fewer lung M2 macrophages.

<p>A. Total lung CD11b⁺ cells following bleomycin administration. B. Total lung CD11b⁺ IFNγ⁺ cells following bleomycin administration. C. Total lung CD11b⁺ CD206⁺ cells following bleomycin administration. D. Arginase1 RNA expression from lung tissue. E. Fizz1 RNA expression from lung tissue. Error bars indicate one standard deviation of the mean and (*) indicates statistical significance (p<.05) between groups. All experiments were performed at least three times, at least 10 animals per group per experiment.</p