Rafael L. Perez

Distribution of Extracellular Matrices, Matrix Receptors, and Transforming Growth Factor-β1 in Human and Experimental Lung Granulomatous Inflammation

Aberrant deposition of extracellular matrices (ECMs) may affect lung inflammation by influencing cell adhesion, migration, and activation. Little is known about the expression of ECMs in lungs with granulomatous inflammation. Therefore the authors investigated the distribution of ECMs, matrix receptors of the integrin family, and transforming growth factor-beta 1 (TGF-beta 1) in lungs from patients with pulmonary sarcoidosis and animals with experimental granulomatosis. Immunohistochemistry revealed increased deposition of type I collagen and fibronectin in human lung granulomas when compared with healthy human lungs. Procollagen type I and cellular fibronectin also were increased, suggesting local synthesis of ECM in sarcoid granulomas. These findings were accompanied by increased staining for fibronectin (alpha 5 beta 1) and collagen (alpha 2 beta 1) integrin receptors. The matrix-inducing cytokine TGF-beta 1 was co-distributed with the aforementioned molecules in the granulomas, whereas no significant staining for TGF-beta 1 was found in healthy lungs. Similar to sarcoid lungs, analysis of lung sections obtained from a murine model of granuloma formation revealed increased expression of fibronectin, collagen, integrin receptors, and TGF-beta 1 within granulomas. Based on these observations, there is increased expression of ECM and matrix receptors in both human and experimental lung granulomas. Such alterations may influence the recruitment and activation of inflammatory cells and fibroblasts, promoting granuloma formation and remodeling of tissue by fibrosis. Activation of mononuclear cells resulting in production of TGF-beta 1 is likely to contribute to the changes described.

Pulmonary Hypertension Idiopathic Pulmonary Fibrosis: A Dastardly Duo

Abstract:Pulmonary hypertension (PH) is a well-recognized complication of interstitial lung disease, including idiopathic pulmonary fibrosis (IPF). The underlying pathogenesis was initially hypothesized to be inflammatory but now is characterized as an over exuberant fibroproliferative process. The prevalence of PH in the setting of IPF has not been well described in the literature, with a reported occurrence from 32% to 85%. Diagnostically, recognizing underlying PH in the setting of IPF remains challenging because of nonspecific clinical symptoms and unrevealing ancillary testing. A high degree of clinical suspicion is paramount. The only reliable diagnostic tool for PH is right heart catheterization. The treatment of PH, in patients with IPF, is based on multiple factors, including disease severity, functional status and degree of hypoxemia. Medications currently approved to treat PH have been administered for PH in the setting of IPF, such as phosphodiesterase-5 inhibitors, nonselective endothelin receptor antagonists and prostacyclin analogues. The treatment of PH in the setting of IPF may also be difficult due to worsening ventilation-perfusion mismatch induced by selective pulmonary artery vasodilator therapy. Lung transplantation should be considered with patients refractory to pharmacological treatment. Identification of PH in IPF patients is crucial, as functional status and prognosis are greatly reduced. Given the high mortality rate and propensity for acute decompensation, IPF and PH patients should be evaluated for transplant early in their disease course.

Management of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disorder characterized by progressive dyspnea, exercise intolerance and, ultimately, respiratory failure and death. The incidence of IPF seems to be increasing, whereas its etiology remains unelucidated. Agents capable of modulating inflammation, kinase pathways, vascular tone, coagulation and fibrosis have been tested in clinical studies although not always in large, randomized, placebo-controlled prospective trials. Despite this effort, a therapy capable of improving survival remains elusive. Consequently, the management of IPF focuses on the early identification of subjects for lung transplantation and on the treatment of comorbidities such as hypoxemia, cough and deconditioning. Until effective therapies are identified, patients and referring physicians are urged to consider participation in well-designed clinical trials.

A 63-Year-Old Man With a Chronic Cough and an Endobronchial Lesion

63-year-old man with an extensive smoking history presented with a complaint of persistent dry cough for 3 months. His past medical history was signifi cant for severe COPD with an FEV 1 at 40% predicted (stage III by GOLD [Global Initiative for Obstructive Lung Disease] criteria). The patient was retired and a current cigarette smoker, and he had no pets. There was no history of prior malignancy or recent travels. He had no fever, night sweats, or weight loss. He was not receiving any angiotensinconverting enzyme inhibitors. There were no symptoms suggestive of upper airway cough syndrome or gastroesophageal refl ux disease. Physical Examination Findings The patient was afebrile with stable vital signs. BP was 127/87 mm Hg, heart rate was 85 beats/min, and oxygen saturation was 94% on room air. A complete physical examination was remarkable for yellow nicotine stains on the fi ngernails without clubbing, wide subcostal angle, distant heart sounds, and prolonged expiratory phase bilaterally, with left-sided monophasic expiratory wheezing best heard over the left upper lobe. Diagnostic Studies CBC was normal, apart from a normocytic anemia, with hemoglobin level of 12 g/dL (normal, 14-18 g/dL). Complete metabolic panel results, includ ing electrolytes, renal, and liver function testing, were within normal limits. No acute abnormalities were detected on chest radiograph. Because of the presence of localized wheezing on physical examination, an endobronchial lesion was suspected, and a CT scan of the chest was obtained. The chest CT scan showed emphysematous changes with an upper lobe predom inance and an ovoid low-density endobronchial lesion in the distal left mainstem bronchus measuring 2.3 cm in maximum diameter ( Fig 1 ).

Pulmonary IgG4+ Rosai-Dorfman disease

Rosai-Dorfman disease (RDD) is a rare non-malignant proliferation of histiocytes of unknown aetiology that mainly affects lymph nodes. Here we report a case of RDD that presented a diagnostic dilemma due to its atypical presentation and the overlap with IgG4 disease. Our case presented with interstitial lung involvement without lymphadenopathy. Open lung biopsy suggested the diagnosis of RDD. However, the predominant IgG4 positive plasma cells together with the absence of lymphadenopathy were not typical of RDD. Within 1 year, the patient developed diffuse lymphadenopathy and immunohistochemical staining of lymph node aspirates confirmed the diagnosis. Despite trials of corticosteroid therapy, the disease progressed.

Postgraduate Education Corner: Pulmonary, Critical Care, and Sleep PearlsA 63-Year-Old Man With a Chronic Cough and an Endobronchial Lesion

63-year-old man with an extensive smoking history presented with a complaint of persistent dry cough for 3 months. His past medical history was signifi cant for severe COPD with an FEV 1 at 40% predicted (stage III by GOLD [Global Initiative for Obstructive Lung Disease] criteria). The patient was retired and a current cigarette smoker, and he had no pets. There was no history of prior malignancy or recent travels. He had no fever, night sweats, or weight loss. He was not receiving any angiotensinconverting enzyme inhibitors. There were no symptoms suggestive of upper airway cough syndrome or gastroesophageal refl ux disease. Physical Examination Findings The patient was afebrile with stable vital signs. BP was 127/87 mm Hg, heart rate was 85 beats/min, and oxygen saturation was 94% on room air. A complete physical examination was remarkable for yellow nicotine stains on the fi ngernails without clubbing, wide subcostal angle, distant heart sounds, and prolonged expiratory phase bilaterally, with left-sided monophasic expiratory wheezing best heard over the left upper lobe. Diagnostic Studies CBC was normal, apart from a normocytic anemia, with hemoglobin level of 12 g/dL (normal, 14-18 g/dL). Complete metabolic panel results, includ ing electrolytes, renal, and liver function testing, were within normal limits. No acute abnormalities were detected on chest radiograph. Because of the presence of localized wheezing on physical examination, an endobronchial lesion was suspected, and a CT scan of the chest was obtained. The chest CT scan showed emphysematous changes with an upper lobe predom inance and an ovoid low-density endobronchial lesion in the distal left mainstem bronchus measuring 2.3 cm in maximum diameter ( Fig 1 ).

Mounier-Kuhn Syndrome. Imaging and Bronchoscopic Findings

A 35-year-old male presented for evaluation of recurrent lower respiratory tract infections. Computed tomography (CT) scan showed tracheobronchomegaly involving the entire trachea and main bronchi. Diverticula were evident mainly in the posterior tracheal wall (Figure 1). Varicose and cystic bronchiectasis extended to the distal bronchi (Figure 2). Serum a1-antitrypsin level, serum IgE level and other serum immunoglobulins levels were normal. Fiberoptic bronchoscopy was consistent with the CT findings (Figure 3). In absence of secondary causes for tracheobronchial enlargement, the diagnosis of Mounier-Kuhn syndrome was made. Mounier-Kuhn syndrome is characterized by tracheobronchial dilation secondary to atrophy of the muscular and elastic tissues in the trachea and main bronchial walls (1). It is more common in men, especially African Americans. Most of the cases are sporadic, but familial cases have been described with a possible recessive inheritance (2). It has three subtypes: type 1 has subtle symmetrical dilation of trachea and major bronchi; type 2 has more obvious dilation with eccentric diverticula; type 3 has diverticula that extend to the distal bronchi. Treatment ranges from respiratory physiotherapy for airway clearance to endobronchial stenting in severe cases (1). n

Pulmonary Necrobiotic Nodules in Crohn's Disease: A Rare Extra-intestinal Manifestation

Pulmonary necrobiotic nodules represent a rare extra-intestinal manifestation of Crohns disease. Histologically, they are composed of sterile aggregates of inflammatory cells with necrosis. The differential diagnosis is broad, and exclusion of infectious etiologies is mandatory before starting immunosuppressive therapy. Here, we present the fifth reported case of pulmonary necrobiotic nodules in Crohns disease. Our patient had new-onset Crohns disease associated with both cavitating and non-cavitating lung nodules that were confirmed to be necrobiotic nodules by biopsy. The patient was started on mesalamine and prednisone, with subsequent improvement of his gastrointestinal symptoms and regression of the necrobiotic nodules.

Smoking-related interstitial fibrosis (SRIF) and pulmonary hypertension.

Smoking-related interstitial fibrosis (SRIF) is a relatively new term used to describe chronic interstitial fibrosis that can develop in smokers. The association of SRIF with pulmonary hypertension has not been described. We present a 55-year-old man with an extensive smoking history who presented for evaluation of insidious onset of dyspnoea on exertion and hypoxaemic respiratory failure. Physical examination was unremarkable. Pulmonary function testing demonstrated a marked reduction of the diffusion capacity with no obstruction or restriction. Ventilation perfusion scan showed no evidence of thromboembolic disease. High-resolution chest CT revealed minimal biapical pleural parenchymal scarring and subtle dependent atelectasis. Serological markers for connective tissue diseases were negative. Open lung biopsy was consistent with SRIF. Vascular intimal proliferation consistent with pulmonary hypertension was also noted. Right heart catheterisation yielded mild pulmonary hypertension and treatment was initiated with tadalafil and bosentan.

A Case of Progressive Lung Fibrosis

Idiopathic pulmonary fibrosis is characterized by progressive fibrosis of the lung and poor prognosis. This is the case report of a patient with idiopathic pulmonary fibrosis that highlights many of the controversies inherent in the diagnosis and treatment of this disease.