Our research focuses on the role of adipose
tissue as a regulator of inflammatory responses. We use experimental
animals, tissue culture and human samples to study how adipocytes and
adipocyte-derived products, such as leptin and adiponectin, regulate
inflammation, particularly in the gastrointestinal tract, liver and
pancreas. This research has translational implications in understanding
why inflammation is more severe in obese people and in trying to
identify novel methods to treat and prevent inflammatory conditions.
The research focus of the laboratory is the study
of adipose tissue and nutrition as regulators of inflammatory and
immune responses. The laboratory is currently involved in three lines
of research:
1. Effect of
obesity on
the outcome of acute pancreatitis and the associated systemic
inflammatory response.
Acute pancreatitis (AP) is
an inflammatory disorder
that can range from a mild edematous form to a severe necrotic
condition that may lead to circulatory shock, acute lung injury, renal
failure, and eventual death.
Despite some controversy, several studies have demonstrated that
obesity is associated with increased risk of the severe necrotic form
of AP and with development of life-threatening complications. However,
the mechanisms by which obesity worsens AP remain unknown.
Interleukin
(IL)-12 and IL-18 are two proinflammatory cytokines that drive the Th1
cell response, characterized by high levels of interferon-gamma. Serum
and pancreatic levels of IL-12 and IL-18 are elevated in patients with
AP and correlate with disease severity. Furthermore, increased levels
of IL-18 are observed in obese subjects.
We developed a novel model of AP
induced by administration of IL-12+IL-18 in mice. We demonstrated that
obese leptin-deficient
ob/ob
mice, as well as mice made obese by feeding a high-fat diet (HFD),
develop severe necrotizing AP in response to IL-12+IL-18, whereas
lean mice respond to these cytokines with development of mild edematous
AP.
We are currently investigating mechanisms leading to increased AP
severity in obesity, focusing on the role played by the cytokine IL-6.
2. Role of adipose
tissue as a modulator of cytokine production and resolution of acute
inflammation in response to microbial stimuli.
The incidence of obesity
and associated comorbidities is dramatically increasing worldwide in
both children and adults. The obese state is characterized by what has
been called low-grade systemic inflammation. In fact, inflammatory
markers, such as C-reactive protein (CRP) and IL-6, are increased in
obese individuals compared with lean subjects. The presence of
systemic inflammation has been linked to the increased risk of
development of cardiovascular disease (CVD) and type II diabetes in
obesity, particularly in the case of visceral adiposity.
Using models of peritonitis, we demonstrated that obesity is associated
with exacerbated and prolonged inflammatory responses, characterized by
the presence of high levels of IL-6 and IL-17 in the peritoneal
fluid. Current work is aimed at identifying the links between
obesity and increased production of IL-17 with plans to translate these
studies to human subjects.
3. In
collaboration with Dr.
Carol Braunschweig, evaluating
the effect of intensive nutritional support in the regulation of immune
and inflammatory parameters in critically ill patients .
It has been demonstrated
that (a) malnutrition in hospital patients is associated with poor
outcomes (b) a large percentage of patients admitted with acute
respiratory distress syndrome (ARDS)are
malnourished, which is exacerbated with prolonged intensive care unit
(ICU) stays, and
nutritional related residual effects remain up to a year post-discharge
(c) morbidity from malnutrition may be related to alterations in immune
response. It has not been demonstrated that malnutrition is
independently associated with poorer outcomes or that enteral nutrition
(EN) (or any
nutritional intervention) provided to malnourished ARDS patients while
hospitalized can (a) improve their nutritional status and (b)
independently improve clinical outcomes.
The Inflammatory Lab is responsible for evaluation of
immune/inflammatory function in this study.
