Study of the Function of Cells Involved in Inflammation in the Lungs of Those With Acute Lung Injury and Sepsis

Acute lung injury (ALI) is a common and lethal form of respiratory failure, occurring in
200,000 people each year and in as many as 25% of mechanically ventilated patients. Despite
multiple clinical studies, there are presently no effective medical therapies for ALI, and
its mortality remains unacceptably high at about 40%. Common co-morbid conditions that can
alter the susceptibility to ALI are chronic alcohol abuse and diabetes mellitus (DM). The
incidence and severity of ALI is increased in critically ill patients with a history of
chronic alcohol abuse. With respect to DM, the group has previously reported that a history
of diabetes mellitus is associated with a decreased incidence of ALI in patients with septic
shock. As the biological mechanism for this association was unknown, a cross-sectional
epidemiological study was conducted by broadly examining the role of diabetes in the
development of respiratory failure associated with sepsis. Using national hospitalization
data, it was found that diabetics with sepsis were less likely to develop any form of acute
respiratory failure than non-diabetics.

ALI occurs through a common pathway of oxidant stress and inflammation, injuring the lungs
and rendering them dysfunctional for gas exchange. The alveolar macrophage (AM) is an
important mediator of the inflammatory response, with roles such as phagocytosis and
secretion of inflammatory cytokines that are key components of lung injury and repair.
While more than one mechanism may explain the previous observations of a decreased incidence
of ALI in diabetics, the data in chronic alcoholics suggests that AM dysfunction may play a
role in the in the development of ALI leading us to hypothesize that DM may similarly alter
the pulmonary microenvironment, thereby decreasing the susceptibility to ALI. Furthermore,
early preliminary data suggests that the AM activity of peroxisome proliferator-activated
receptor gamma (PPARγ), a transcription factor with anti-inflammatory properties, may be
increased in diabetics. In addition, evidence suggests that macrophage activation into a
pro-inflammatory versus an anti-inflammatory state may be tissue specific and altered by
obesity and insulin resistance (i.e. compartmentalized in the lung). However, the effect of
DM on the pulmonary inflammatory response and specifically AM function is as yet unknown.
PPARγ is highly expressed in AMs, and thus PPARγ ligands have direct affects on AMs to
influence lung inflammation by inhibiting oxidative burst and enhancing AM phagocytic
function. PPARγ and its ligands influence AM differentiation into M1 (pro-inflammatory) and
M2 (anti-inflammatory) phenotypes and a recent preclinical study demonstrated effective
prevention of ALI by pretreatment with a PPARγ ligand. However, the effect that DM and
PPARγ ligands have on AM phenotypic differentiation, PPARγ expression, oxidative stress and
AM phagocytic function has not been well investigated. To our knowledge, there is no data
on AM PPARγ activity in DM, and little is known about how this disease state may alter the
pulmonary inflammatory milieu. The investigators hypothesize that DM reduces the risk of
ALI by modulating AM differentiation and function via PPARγ expression, oxidative stress and
AM phagocytic function, which may be positively influenced by exposure to a PPARγ ligand.
Examining the impact of DM and PPARγ on AM phenotype and function may identify mechanisms
responsible for the decreased incidence of ALI in diabetics; improve our understanding of
the pathogenesis of a common and lethal disease, and lead to novel therapies for both
diabetic and non-diabetic critically ill patients

Inclusion Criteria:

Patients within the first 72 hours of development of severe sepsis or septic shock

Exclusion Criteria:

1. No informed consent

2. Pregnancy

3. Expected survival ≤ 72 hours

4. Not mechanically ventilated

5. Age < 18 years