Clara Cell Secretory Protein Modulates Lung Inflammatory and Immune Responses to Respiratory Syncytial Virus Infection

Abstract

Clara cell secretory protein (CCSP) has been shown to have anti-inflammatory and immunomodulatory functions in the lung. Respiratory syncytial virus (RSV) is the most common cause of respiratory infection in infants and young children. RSV usually infects small airways and likely interacts with the Clara cells of bronchioles. To determine a possible role for CCSP during acute RSV infection, CCSP-deficient (CCSP−/−) and wild-type (WT) mice were intratracheally infected with RSV and the lung inflammatory and immune responses to RSV infection were assessed. RSV-F gene expression was increased in the lungs of CCSP−/− mice as compared with WT mice following RSV infection, consistent with increased viral persistence. Lung inflammation was significantly increased in CCSP−/− mice as compared with WT mice after infection. Moreover, although the levels of Th1 cytokines were similar, the levels of Th2 cytokines and neutrophil chemokines were increased in the lungs of CCSP−/− mice following infection. Physiologic endpoints of exacerbated lung disease, specifically airway reactivity and mucus production, were increased in CCSP−/− mice after RSV infection. Importantly, restoration of CCSP in the airways of CCSP−/− mice abrogated the increased viral persistence, lung inflammation, and airway reactivity. These findings suggest a role for CCSP and Clara cells in regulating lung inflammatory and immune responses to RSV infection.

Urine Club Cell 16-kDa Secretory Protein and Childhood Wheezing Illnesses After Lower Respiratory Tract Infections in Infancy

“…43,44 Following acute viral infections, transgenic mice deficient in CC16 develop a more severe lung inflammation with increased Th2 cytokine levels, airway reactivity, and mucous production, as well as prolonged viral persistence. 45,46 Reconstitution of CC16 in mice is able to reverse these altered phenotypes. 46 The CC16 gene maps to a genetic region (11q12-13) that has been linked to asthma and atopy in some studies.…”

“…45,46 Reconstitution of CC16 in mice is able to reverse these altered phenotypes. 46 The CC16 gene maps to a genetic region (11q12-13) that has been linked to asthma and atopy in some studies. 47,48 The A38G polymorphism in the promoter region of this gene decreases the amount of expressed CC16 and has been found to be associated with wheezing disorders in children and adults.…”

IL-12p40 and IL-18 Modulate Inflammatory and Immune Responses to Respiratory Syncytial Virus Infection

“…A syringe containing inoculant was expelled into the trachea followed by multiple injections of air to facilitate dispersion of inoculant into the lung periphery. Mice usually recovered within 5 min and resumed normal eating and grooming activities (26,27). Sterile medium (100 l/mouse) was used as control.…”

“…instillations of 0.6 ml of PBS into the right lung using a fine catheter tied to the right main bronchus, and the samples were pooled for each animal. The BALF was processed, and the total and differential cells were counted as described elsewhere (26,27). The remaining lung tissues were then used for histopathological and molecular studies as described below.…”

Advances in emerging treatment options to prevent bronchopulmonary dysplasia

“…In addition, it inhibits secretory phospholipase A2, an enzyme which degrades surfactant and facilitates prostaglandin biosynthesis [58]. Transgenic mice deficient in CCSP have been demonstrated to have exaggerated pulmonary inflammatory responses to hyperoxia and higher mortality rates [59]. Intra-tracheal treatment with exogenous CCSP tended to improve gas exchange and lung compliance in newborn piglets exposed to a hyperoxic injury [60].…”