Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling.

Rationale: Severe pulmonary arterial hypertension (SPH) is a frequently lethal condition characterized by pulmonary vascular remodeling and right heart strain or failure. SPH is also often associated with autoimmune and collagen vascular disorders.

Objectives: To study the effects of T cells on the development of experimental SPH.

N-acetylcysteine treatment protects against VEGF-receptor blockade-related emphysema.

Administration of the VEGF receptor blocker SU5416 to rats causes alveolar septal cell apoptosis and emphysema; both can be prevented by a superoxide dismutase mimetic. Here we show that SU5416 induces the expression of heme oxygenase-1 in the lung tissue and that administration of antioxidant N-acetyl-l-cysteine protects alveolar septal cells against apoptosis, as demonstrated by caspase-3 lung immunohistochemistry, and against emphysema.

Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension.

Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH.

A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary emphysema.

Rationale: There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of alpha1-antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke-induced emphysema.

Objectives: We propose that, in addition to its antielastolytic effects, alpha1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis.

Treatment of severe pulmonary hypertension: a bradykinin receptor 2 agonist B9972 causes reduction of pulmonary artery pressure and right ventricular hypertrophy.

Bradykinin is an important modulator of endothelial cell function and has also a powerful cardioprotective effect. Here we report that treatment of severely pulmonary hypertensive rats (that recapitulate several of the physiological and pathological characteristics of the human pulmonary vascular disease, including dramatic right ventricular hypertrophy, pericardial effusion and death) with a newly synthesized long-acting bradykinin B2 receptor agonist B9972 caused reduction of the pulmonary artery pressure (PAP=51+/-2.0 versus 68+/-2.

An animal model of autoimmune emphysema.

Although cigarette smoking is implicated in the pathogenesis of emphysema, the precise mechanisms of chronic progressive alveolar septal destruction are not well understood. We show, in a novel animal model, that immunocompetent, but not athymic, nude rats injected intraperitoneally with xenogeneic endothelial cells (ECs) produce antibodies against ECs and develop emphysema. Immunization with ECs also leads to alveolar septal cell apoptosis and activation of matrix metalloproteases MMP-9 and MMP-2.

Life after corpse engulfment: phagocytosis of apoptotic cells leads to VEGF secretion and cell growth.

Removal of apoptotic cells by neighboring viable cells or professional phagocytes is essential for the maintenance of tissue homeostastis. Here we show that the phagocytosis of apoptotic Jurkat T cells by mouse epithelial cells (HC-11) and peritoneal macrophages leads to the secretion of growth and survival factors. We characterized VEGF as one of these factors which subsequently promote the proliferation of endothelial cells.

Methylprednisolone causes matrix metalloproteinase-dependent emphysema in adult rats.

Previous investigations have shown that corticosteroids affect the development and maturation of the developing lung in utero and in neonatal animals. Systemic corticosteroids are routinely used for the treatment of acute exacerbations of chronic obstructive pulmonary disease, and inhaled corticosteroids are more frequently being prescribed for the long-term treatment of patients with chronic obstructive pulmonary disease. Because corticosteroids can affect matrix metalloproteinases and because the concept of protease/antiprotease imbalance is an important concept regarding the pathogenesis of emphysema, we examined the effects of chronic steroid treatment on lung structure in adult rats.