Bacterial Infections and Mycoses; Immune System Diseases; Respiratory Tract Diseases
Dr. Britto's research focuses on the role of the novel protein SPLUNC1 in the immunity of the respiratory tract. SPLUNC1 (Short Palate Lung and Nasal Epithelial Clone 1) is produced in the lining of the large airways, a location constantly exposed to infectious agents and irritants.
SPLUNC1 is one of the most abundantly secreted products of the respiratory tract and has antimicrobial and anti-inflammatory functions. It also participates in the maintenance of the airway surface liquid, the liquid layer that covers the airways, an important protective mechanism against infection.
The functions of SPLUNC1 suggest it is critical to maintain a healthy respiratory tract. Some of these functions are dramatically impaired in patients with cystic fibrosis (CF), where chronic airway inflammation, poor secretion clearance and recurrent infections are prominent features of their clinical course. Dr. Britto's interest is in understanding how high levels of SPLUNC1 in CF may contribute to the development of airway disease.
Extensive Research Description
Short Palate Lung and Nasal epithelium Clone 1 (SPLUNC1) is an abundant airway protein with host protective functions relevant to cystic fibrosis (CF), the most common fatal genetic disease in the United States. The antimicrobial defense, mucociliary clearance and ion tranport regulation properties of SPLUNC1 may be important in the development of CF lung disease, the main cause of mortality in these patients. Persistent pulmonary inflammation and neutrophilic infiltration are hallmarks of CF lung disease. Work in our laboratory suggests that SPLUNC1 may have a novel role in regulating neutrophilic airway inflammation, as SPLUNC1-deficient (splunc1-/-) mice have dramatically decreased airway neutrophils during acute inflammation induced by LPS compared to wild type (WT) littermates.
SPLUNC1 is decreased in the airways of patients during allergic inflammation and we have shown that SPLUNC1 is decreased by common respiratory pathogens in animal models of airway inflammation in vivo, and by interferon gamma in vitro. Interestingly, this suppression of SPLUNC1 appears to be impaired in lung explants of severe CF patients undergoing lung transplantation, where SPLUNC1 is increased despite chronic inflammation and infection. In preliminary work, we determined that the suppression of SPLUNC1 is also impaired in the bronchoalveolar lavage fluid (BALF) of unstimulated CFTR-deficient (cftr-/-) and F508del homozygous (F508del) mice, two animal models of CF indicating that these animal models may be useful to study the regulation of SPLUNC1 in CF.
Despite the apparent paradox between the pathological and protective role of SPLUNC1, little is known about the mechanisms that regulate its activity, the role that SPLUNC1 plays in neutrophilic inflammation and its sigificance in the development of CF lung disease. We believe that the suppression of SPLUNC1 is a protective mechanism to limit neutrophilic inflammation and subsequent airway injury and so, high SPLUNC1 in CF may be detrimental by promoting neutrophilic inflammation, a fundamental part of CF lung disease pathogenesis. The objective of our research program is to understand how SPLUNC1 influences neutrophilic airway inflammation and if the modulation of SPLUNC1 can limit airway inflammation in CF.
Regulation of SPLUNC1 expression by the airway epithelium: identification of mechanisms by which pathogens, PAMPs and cytokines modulate SPLUNC1 expression.
Mechanisms of neutrophilic inflammation control by SPLUNC1: characterization of the role of SPLUNC1 in neutrophil recruitment to the lungs during acute airway inflammation.
Role of SPLUNC1 in immune responses in CF: defining mechanisms by which SPLUNC1 is increased in CF and what effect this increase has in neutrophilic immune responses.
- Britto CJ, Cohn L. BPIFA1 (SPLUNC1) in Airway Host Protection and Respiratory Disease. Am J Respir Cell Mol Biol. 2014 Sep 29. [Epub ahead of print] PMID: 25265466 [PubMed - as supplied by publisher]
- Britto CJ, Liu Q, Curran DR, Patham B, DeLa Cruz CS, Cohn L. SPLUNC1 is a tightly regulated airway sensor in innate and adaptive immunity. Am. J. Resp. Cell Mol. Biol. 2013 Jun;48(6):717-24. doi: 10.1165/rcmb.2012-0072OC